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Rapid and Self-Administrable Capillary Blood Microsampling Demonstrates Statistical Equivalence with Standard Venous Collections in NMR-Based Lipoprotein Analysis

  • Jayden Lee Roberts
    Jayden Lee Roberts
    Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia
    Centre for Computational and Systems Medicine, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia
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    Orcidhttps://orcid.org/0000-0003-2236-2945
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  • Luke Whiley
    Luke Whiley
    Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia
    Centre for Computational and Systems Medicine, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia
    More by Luke Whiley
    Orcidhttps://orcid.org/0000-0002-9088-4799
  • , 
  • Nicola Gray
    Nicola Gray
    Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia
    Centre for Computational and Systems Medicine, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia
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    Orcidhttps://orcid.org/0000-0002-0094-5245
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  • Melvin Gay
    Melvin Gay
    Bruker Pty Ltd., Preston, VIC 3072, Australia
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  • Philipp Nitschke
    Philipp Nitschke
    Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia
    Centre for Computational and Systems Medicine, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia
    More by Philipp Nitschke
    Orcidhttps://orcid.org/0000-0002-5814-7529
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  • Reika Masuda
    Reika Masuda
    Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia
    Centre for Computational and Systems Medicine, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia
    More by Reika Masuda
  • , 
  • Elaine Holmes
    Elaine Holmes
    Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia
    Centre for Computational and Systems Medicine, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia
    Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, South Kensington, London SW7 2AZ, U.K.
    More by Elaine Holmes
    Orcidhttps://orcid.org/0000-0002-0556-8389
  • , 
  • Jeremy K. Nicholson*
    Jeremy K. Nicholson
    Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia
    Centre for Computational and Systems Medicine, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia
    Department of Cardiology, Fiona Stanley Hospital, Medical School, University of Western Australia, Murdoch, WA 6150, Australia
    Institute of Global Health Innovation, Faculty of Medicine, Imperial College London, Level 1, Faculty Building, South Kensington, London SW7 2NA, U.K.
    *Email: [email protected]
    More by Jeremy K. Nicholson
    Orcidhttps://orcid.org/0000-0002-8123-8349
  • , 
  • Julien Wist*
    Julien Wist
    Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia
    Centre for Computational and Systems Medicine, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia
    Faculty of Medicine, Department of Metabolism, Digestion and Reproduction, Division of Digestive Diseases, Imperial College, London SW7 2AZ, United Kingdom
    Chemistry Department, Universidad del Valle, Melendez 76001, Cali, Colombia
    *Email: [email protected]
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    Orcidhttps://orcid.org/0000-0002-3416-2572
  • , and 
  • Nathan G. Lawler*
    Nathan G. Lawler
    Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia
    Centre for Computational and Systems Medicine, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia
    *Email: [email protected]
    More by Nathan G. Lawler
    Orcidhttps://orcid.org/0000-0001-9649-425X
Cite this: Anal. Chem. 2024, 96, 11, 4505–4513
Publication Date (Web):February 19, 2024
https://doi.org/10.1021/acs.analchem.3c05152

Copyright © 2024 The Authors. Published by American Chemical Society. This publication is licensed under

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Abstract

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We investigated plasma and serum blood derivatives from capillary blood microsamples (500 μL, MiniCollect tubes) and corresponding venous blood (10 mL vacutainers). Samples from 20 healthy participants were analyzed by 1H NMR, and 112 lipoprotein subfraction parameters; 3 supramolecular phospholipid composite (SPC) parameters from SPC1, SPC2, and SPC3 subfractions; 2 N-acetyl signals from α-1-acid glycoprotein (Glyc), GlycA, and GlycB; and 3 calculated parameters, SPC (total), SPC3/SPC2, and Glyc (total) were assessed. Using linear regression between capillary and venous collection sites, we explained that agreement (Adj. R2 ≥ 0.8, p < 0.001) was witnessed for 86% of plasma parameters (103/120) and 88% of serum parameters (106/120), indicating that capillary lipoprotein, SPC, and Glyc concentrations follow changes in venous concentrations. These results indicate that capillary blood microsamples are suitable for sampling in remote areas and for high-frequency longitudinal sampling of the majority of lipoproteins, SPCs, and Glycs.

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Introduction

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Metabolic phenotyping provides a means to capture an integrated profile of an individual’s biological status and reflects the interaction of genes and the environment, especially in response to external stressors. (1,2) Nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) are the lead platforms to provide high-fidelity dense information about a variety of biomolecules. Robust protocols have been developed, validated, and standardized for various biofluids (e.g., plasma, serum, urine, tissue, etc.). Typically, most clinical studies have relied on conventional venous phlebotomy to acquire samples. However, sampling should be as simple and safe as possible to be clinically relevant. In the case of venous blood collection, a trained phlebotomist is required to perform the tightly regulated procedure to avoid adverse outcomes. To understand the mechanisms of disease or responses to therapeutic interventions, recording the behavior of specific molecules over time contributes valuable information. However, frequent vein puncture must also be avoided, and although a cannula can be used for repeated sampling, it must remain clean and dry, making it ill-suited beyond controlled settings. In contrast, capillary blood microsamples have a collection volumes (typically less than 50 μL, although volumes can extend up to 600 μL) (1) that offer a minimally invasive alternative to traditional intravenous sampling, which supports the evolving nature of healthcare from reactive disease care to care that is predictive, preventive, personalized, and participatory (P4 medicine). (1,3,4) Capillary microsampling is performed by lancing the fingertip for collection of blood drops into a small container or blood collection card, making increased sampling frequencies possible. Many advanced devices are also commercially available with volumes that are suitable for standard metabolic profiling protocols. (1)
1H NMR spectroscopy has long been used for the measurement of variable biochemical signatures of blood plasma and serum to understand health and disease. (5−9) This includes analysis of panels of lipoproteins, supramolecular phospholipid composites (SPCs), and glycoprotein acetyls (α-1-acid glycoproteins) and others, which offer a diagnostic tool that extends beyond the standard clinical assays for low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol. These parameters can be acquired in less than 5 min and require minimal sample preparation. (10) Quantification is achieved by regression of several key regions of a standard NMR spectrum using mathematical models. (11) Using the B.I. LISA analytical model, Lodge et al. previously concluded that 3 mm NMR tubes (that utilize 100 μL of plasma) are well-suited for deriving quantitative measurements, especially when working with samples of limited volume, compared to 5 mm tubes (utilizing 300 μL of plasma). (12) However, the use of 3 mm tubes necessitates extended scan times (15 min per sample per experiment) and spectra with reduced signal-to-noise when compared to 5 mm tubes (4 min). Modified spectroscopic methods have also been proposed for direct measurement of SPCs and Glycs in plasma or serum without the need for complex statistical modeling or peak deconvolution. (7,13−17) Recently, some of those experiments have been successfully translated to benchtop NMR spectrometers. (18)
Lipoprotein assemblies transport water-insoluble lipids such as cholesterol and glycerolipids in blood and are crucial to understanding the etiology and pathophysiology of diseases hallmarked by lipid and lipoprotein metabolism dysregulation, such as cardiometabolic and neurological diseases. (11) Previously, decreased levels of total cholesterol (TC), HDL-C, LDL-C, and increased triglycerides (TGs) have been shown to be positively correlated with cardiovascular disease severity (19) and increased levels of the apolipoprotein B100/apolipoprotein A1 ratio has been associated with atherogenic risk. (20,21) SPC has also been shown to decrease during acute inflammation while GlycA and GlycB demonstrate increases; hence, the SPC/Glyc (total) ratio has been proposed as a marker of inflammation. (22,23) Of the latter two, the SPC signal refers to trimethylammonium residues in supramolecular phospholipid components of lipoproteins, which result in three signal components: SPC1, SPC2, and SPC3, representing the phospholipid content of HDL-4, phospholipids from HDL-1, -2 and -3, and phospholipids from LDL particles, respectively. (24) And Glyc refers to the N-acetyl methyl group signals, including GlycA and GlycB, which represent glycosylated amino sugars in side chains of a composite of inter alia five main acute phase glycoproteins: α-1-acid glycoprotein, α-1-antichymotrypsin, α-1-antitrypsin, haptoglobin, and transferrin, all of which are associated with inflammation. (25)
Whole blood, separated into either plasma or serum, is a commonly used blood derivative in metabolic phenotyping research for lipoproteins, SPCs, and Glycs. Previously, in vitro proteolysis during the serum clotting process (26,27) and increased osmosis caused by plasma tube anticoagulants (28,29) have been thought to play a role in lipoprotein differences observed between blood collection tubes (i.e., serum vs plasma). Despite only concerted reductions in apolipoprotein B-100, (29) lipoprotein a Lp(a), and antiapolipoproteins (a) and (b) (30) being shown previously, their variation has been thought to be based on small biological differences between plasma and serum blood derivatives. Specifically, plasma is the top protein-rich layer in a suspension derived from the centrifugation of whole blood, below which is a buffy coat of leukocytes and platelets, followed by erythrocytes, whereas serum is the remaining fluid following the removal of the clot from whole blood. Composition-wise, serum excludes the fibrinogens and clotting factors present in plasma, and as such, contains less protein. (28,29) In this context, the recent proton NMR-based lipoprotein studies by Loo et al. (31) demonstrated that the effect of blood collection tubes on lipoprotein profiles was trivial. Thus, highlighting the similar nature of plasma and serum blood derivatives for lipoprotein quantification.
Although the impact of different venous blood collection tubes on the quantification of lipoproteins has been studied, (32) much less is known about the impact of sampling different sites (i.e., fingertip capillary). Capillary sample dilution is hypothesized to occur from the combination of blood serum or plasma with interstitial fluid, likely as a result of sample collection under pressure from the lancing site. (33) For instance, Kupke et al. reported lower levels of lipoproteins (34) and metabolites, (35) respectively, in capillary blood microsamples compared to matched venous samples, whereas Sedgwick et al. previously employed an enzymatic colorimetric assay using EDTA-treated plasma samples and found no notable differences between capillary and venous lipoprotein concentrations. (36) With advancements in high-resolution methodologies capable of lipoprotein subclass quantitation, our study aimed to provide a more accurate and comprehensive understanding of collection site differences.

Experimental Design

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Study Participants

Twenty healthy volunteers, 10 men (age: 33 ± 17 (SD) years) and 10 women (age: 40 ± 22 (SD) years), were recruited from Perth, Western Australia, to participate in this study (Figure 1). Participants were included if they were over 18 years old and willing to provide both capillary and venous blood samples. Exclusion criteria included conditions where blood collection may be hazardous (e.g., hemophilia). The study was approved by the Human Research Ethics Committee at Murdoch University (Ethics no. 2022/119) and complied with the guidelines from the Declaration of Helsinki. Informed consent forms were obtained from each participant prior to their participation in the study. For the high-field analysis, blood was collected from 20 participants for comparison of capillary and venous collection sites (Figure 1A), and 12/20 participants were on a later date for a venous replicate 3-day assessment (Figure 1B). For the low-field preliminary analysis, two out of 20 participants had a final collection for capillary and venous collection sites (Figure 1C).

Figure 1

Figure 1. Sample collection workflow for 1H NMR. (A) Evaluating the comparability between venous and capillary blood sampling sites; (B) 3-day assessment of venous technical replicate standard error for 3 mm outer diameter SampleJet NMR tubes; (C) preliminary comparison of low-field spectra: (V) = venous, (C) capillary, (s) = serum, and (p) = plasma. Image created with BioRender.com.

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Blood Collection Protocol for Human Serum and Plasma

Participants attended the clinic following a 12 h overnight fast for the collection of blood samples. Venous collections included whole blood using a 23-gauge needle into two types of Becton Dickinson (BD) vacutainer tubes taken from the antecubital fossa (1 × 10 mL of serum clot activation tube (CAT) and 1 × 10 mL of lithium heparin (LH) tube). Capillary blood microsampling included 0.5 mL MiniCollect tubes for both CAT and LH that were taken from the index finger (of the same arm venous blood was collected from) using lancets. A hand-warming procedure was used to promote blood circulation and ensure sufficient volume collection for the latter. Here, participants were instructed to immerse their hand in a bucket of warm water for ∼2 min. The hand was removed and dried thoroughly. An alcohol wipe was then used to prepare the index finger for lancing with a single-use AccuChek Safe-T-Pro-Plus lancet set to the greatest depth (2.3 mm). Draws were performed sequentially as follows: venous serum and plasma, followed by capillary serum and plasma. Immediately following collection, all samples were left at room temperature for 1 h (allowing the serum samples to clot). Collection of all samples was completed within <20 min. Samples underwent centrifugation at 4 °C for 10 min at 1300g. The resulting plasma/serum layer was aliquoted into cryo-vials and stored at −80 °C until the commencement of sample preparation. Blood samples were processed and frozen within 2 h of collection. A second visit for 12/20 participants collected 2 × 10 mL LH tubes, and a final visit for 2/20 participants collected 1 × 10 mL LH and 1 × 0.5 mL MiniCollect LH tube.

Sample Preparation

Samples were thawed on ice and prepared following an established protocol, as described elsewhere. (13) In brief, samples were centrifuged at 13,000g for 10 min at 4 °C to remove any remnant particulate before loading an equal mixture of phosphate buffer (75 mM Na2HPO4, 2 mM NaN3, 4.6 mM sodium trimethylsilyl propionate-[2,2,3,3-2H4] (TSP) in H2O/D2O 4:1, pH 7.4 ± 0.1) into each plasma and serum sample at a 1:1 ratio for a final volume of up to 200 μL. The final volume was transferred to 3 mm NMR SampleJet tubes from the same batch, which were then sealed by adding POM balls to their caps. Samples were manually shaken to remove any bubbles present in the tubes and then stored at 5 °C inside the SampleJet automatic sample changer until measurement (<24 h).

High-Field 1H NMR Spectroscopy Data Acquisition and Data Analysis

NMR analysis was performed using a 600 MHz Bruker Avance III HD spectrometer equipped with a 5 mm BBI probe and fitted with a Bruker SampleJet robotic cooling system set at 5 °C. A full quantitative calibration was completed prior to analysis using a previously described protocol for high-throughput proton NMR spectroscopy on plasma and serum. (13) Measurements for each sample included a standard 1D experiment performed with solvent presaturation (128 scans, 98k data points, spectral width (sw) of 30 ppm), and a J-Edited DIffusional (JEDI) pulsed gradient perfect echo (PGPE) experiment (256 scans, 98k data points, sw 30 ppm). (24) In total, data collection took 31 min per sample, which were processed in automation mode using Bruker Topspin 3.6.3 and ICON NMR to achieve phasing, baseline correction, and calibration to TSP.
Quantification of 112 parameters of the main plasma and serum lipoprotein classes and subclasses using Bruker’s IVDr Lipoprotein Subclass Analysis (B.I. LISA, version PL-5009-01/001) method was performed. (11) The platform applied a regression model to 1H NMR spectra with solvent suppression to compute the concentration of triglycerides (-TG), cholesterol (-CH), free cholesterol (-FC), phospholipids (-PL), Apo A1 (-A1), Apo-A2 (-A2), and Apo B100 (-AB) of the main very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), LDL, and HDL classes. (11) The full B.I. LISA parameters and lipoprotein densities have been detailed (Table S1). Four further parameters were measured using Bruker’s IVDr PhenoRisk PACS for research use only (RUO) method comprising 3 Glyc parameters and one SPC parameter associated with inflammatory responses. (14,37−39) From the latter, SPC1, SPC2, and SPC3 subfractions and related parameters were measured according to a procedure described elsewhere. (40)

Low-Field 1H NMR Spectroscopy Data Acquisition and Data Analysis

SPC and Glyc comparison was performed manually by acquiring capillary and venous plasma samples in 3 mm 7 inch NMR tubes using an 80 MHz Bruker Fourier 80 (F80) spectrometer. Measurements for each sample included a standard 1D experiment performed with solvent presaturation (96 scans, 23,808k data points, spectral width of 30 ppm) and a JEDI pulsed gradient spin echo (PGSE) experiment (512 scans, 3224k data points, sw 20 ppm). (18) In total, data collection took 45 min per sample and datawere processed using Bruker Topspin 4.3.0 to achieve phasing, baseline correction, and calibration to TSP.

Statistical Analysis

Statistics and data visualizations were performed using R version 3.4.1 and RStudio. (41) For all parameters, the correspondence between capillary and venous plasma samples was determined using simple linear regression. Adjusted R2 and p-values were derived from the linear model to determine the goodness-of-fit between the capillary and venous samples. Adjusted R2 ≥ 0.8 was interpreted as strong, values between 0.5 and 0.79 were interpreted as moderate, and values below 0.5 were interpreted as weak. For each parameter, mean value, variance (using the squared difference and adjusting by the degrees of freedom), and standard deviation were computed. Finally, the standard error percentage was calculated by dividing the standard deviation by the mean value and then multiplying by 100. To help with the interpretation of the resulting standard error percentages, those were contrasted with values obtained for technical replicates acquired for 3 consecutive days using venous blood.

Results

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To assess if capillary blood microsample collections were amenable for NMR lipoprotein measurement, we compared quantitative concentrations of lipoproteins, SPCs, and Glycs using 1H NMR spectroscopy on two common biofluids derived from whole blood collections (plasma and serum), which were collected from capillary and venous collection sites. The demographics for the recruited cohort, including age, sex, weight, height, and BMI, are presented in Table 1. A complete list of the measured lipoproteins, SPCs, and Glycs is reported in Table S1. One sample was removed from the serum data set prior to any statistical analysis due to a failed quality control check, where less than the required 100 μL of plasma was collected. In total, 112 complete lipoproteins and lipoprotein subclasses were quantified as well as a set of inflammatory composite signals for measures of the SPC and Glyc parameters.
Table 1. Participant Demographics
healthy controls women men total
N 10 (50%) 10 (50%) 20 (100%)
age, years [SD] 40 [±22] 33 [±17] 37 [±20]
weight, kg [SD] 61.8 [±9.38] 72.05 [±12.72] 66.93 [±12.08]
height, cm [SD] 160.0 [±8.52] 177.1 [±5.22] 168.6 [±11.15]
BMI [SD] 24.59 [±6.02] 22.95 [±3.76] 23.77 [±4.96]

Evaluating Equivalence and Variation Between Capillary and Venous Collection Sites

The median spectra from the JEDI-PGPE experiments exhibited a high degree of similarity in SPC and Glyc signatures between capillary and venous samples in both plasma and serum (Figure 2) when overlaid. In serum samples, a small difference in the low-frequency portion of SPC was witnessed. This region corresponds to HDL-4, which demonstrated less explained variance between collection sites in the lipoprotein assay, as expected from the 1D spectra and Adj. R2 (Figure 3─serum). For plasma samples, the difference in SPC intensity between collection sites was smaller, corresponding with a stronger relationship in HDL-4 between capillary and venous collection sites (Figure 3─plasma).

Figure 2

Figure 2. Median proton NMR spectra from all study participants for 1D and JEDI-PGPE experiments. Plasma and serum represent spectra of the capillary and venous samples collected from a clinical visit (N = 20). Capillary spectra (green and red traces) are overlaid with venous (black traces) derived in the 1D and PGPE experiments. Expansions of the SPC and Glyc regions from the latter demonstrate an overlap between capillary and venous samples in both plasma and serum. In serum samples, a small difference in the low-frequency portion of SPC1, corresponding to HDL-4, is witnessed. 3-Day replicates represent spectra of venous plasma collected from two clinical visits (N = 12).

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Figure 3

Figure 3. Relationship and variation of plasma and serum analyte concentrations between the different collection sites. Adjusted R2 for plasma (green) and serum (red) with corresponding standard error percentage (SE%, black) for capillary vs venous lipoproteins (LIPO, VLDL, LDL, HDL), supramolecular phospholipid composites (SPCs), and glycoprotein acetyls (Glycs) parameters. For plasma, collection site SE% is overlaid with SE% of 3-day replicates of venous plasma acquired in 3 mm outer diameter NMR SampleJet tubes (blue). Hollow circles indicate parameters where the standard error percentage is lower for the 3-day 3 mm venous plasma analysis than the error between venous and capillary and Adj. R2 < 0.80. For serum, only the latter rule applies. A descriptive list of the abbreviated lipoprotein main fractions, subfractions, SPCs, and Glycs (gray labels) are reported in Table S1.

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A linear regression model was constructed for each parameter to investigate the relationship between values obtained from different collection sites for both plasma and serum tubes. Additionally, an assessment of analytical variation between capillary and venous collection sites was conducted by calculating the standard error percentage (Figure 3). Explained variance (Adj. R2 ≥ 0.8, p < 0.001) was witnessed for 86% of plasma analytes (103/120) and 88% of serum analytes (106/120), indicating that the capillary blood analyte concentration follows changes in venous analyte concentration. A further 13% of plasma analytes (15/120) and the remaining 12% of serum analytes (14/120) achieved moderately significant linear relationships (50% > R2 > 79%, all p ≤ 0.001) between collection sites (Figure 3). Notably, the collection site left all main fractions─clinically widely used parameters such as LDL cholesterol (LDCH) and HDL cholesterol (HDCH)─unaffected with goodness-of-fit ranging from Adj. R2 = 0.929 (p < 0.001) for plasma HDCH to Adj. R2 = 0.969 (p < 0.001) for serum LDCH. The ratio between apolipoprotein B100 and apolipoprotein A1 (ABA1), an important marker for atherogenic risk, also exhibited excellent agreement between the two collection sites in plasma (Adj. R2 = 0.968, p < 0.001) and serum (Adj. R2 = 0.967, p < 0.001).

Technical Replicates Using Venous Blood in 3 mm 1H NMR SampleJet Tubes

Of the parameters achieving an adjusted R2 < 0.8 between capillary and venous collection sites, smaller errors were witnessed in venous plasma replicate 3 mm measurements of five very high-density parameters of LDL (L6PN, L6CH, L6FC, L6PL, L6AB) and two very high-density parameters of HDL (H3FC, H4FC) over the course of the 3 days of NMR sample preparation (Figure 3─plasma).

Capillary SPC and Glyc Direct Measurement with Benchtop Low-Field 80 MHz NMR

To preliminarily assess the capillary translatability of SPC and Glyc biomarkers of inflammation, we performed the analysis of two sets of capillary and venous plasma samples on benchtop low-field 80 MHz NMR (Figure 4). A small difference between capillary and venous samples for participant one was observed in the 1D experiment. In the JEDI-PGSE experiment, overlap was demonstrated in both participants between their respective capillary and venous plasma samples using the raw traces for SPC and Glyc measurements.

Figure 4

Figure 4. Preliminary direct low-field 80 MHz 1H NMR spectra. 1D and JEDI-PGSE spectra of capillary (green trace) and venous (black trace) plasma samples collected from two participants (PT.1 = left, PT.2 = right). Capillary spectra overlay with venous spectra for SPC and Glyc measurements from the PGSE experiment.

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Discussion

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We compared 112 quantified lipoproteins and 8 inflammatory SPC and Glyc parameters obtained for plasma and serum samples from venous and capillary blood. Spectra acquired from both capillary and venous sampling sites were shown to be equivalent for all quantitative parameters, specifically, with 86% (103/120) of measurements in plasma and 88% (106/120) in serum, reporting strong significant relationships (adjusted R2 ≥ 0.8). Similarly, Sedgwick et al. reported no significant differences between capillary and venous plasma lipid and lipoprotein measurements, albeit delimited to traditional cholesterol, HDL cholesterol, LDL cholesterol, and total triglyceride clinical markers using an enzymatic colorimetric assay. (36) Importantly, markers such as total plasma triglycerides, apolipoprotein A1, and SPCs that have been identified as biomarkers of cardiovascular risk related to both acute and chronic inflammation (40) were found highly correlated between the two sampling sites. These results indicate that self-administrable microcapillary blood collections are a suitable alternative to venous blood collections.
Results from this study revealed that experimental errors observed are similar between capillary and venous plasma collection sites. Eight parameters failed to reach an adjusted R2 of ≥0.8 and had lower standard error percentages among venous plasma technical replicates than those witnessed between capillary and venous plasma collection sites. Specifically, this concerned two parameters of HDL (H3FC, H4FC) and six parameters of LDL (L2TG, L6PN, L6CH, L6FC, L6PL, L6AB). The former refer to small, high-density parameters within their respective lipoprotein subfractions that are not commonly employed in standard clinical assessments. Recent studies have identified differences in some of these parameters in conditions such as SARS-CoV-2 infection, (22,42) type 2 diabetes mellitus, (43) diet, (44) and the postprandial response. (45) However, only venous collections were utilized, limiting direct comparability to the present findings. These parameters were unable to pass the arbitrary criteria of adjusted R2 ≥ 0.8─a threshold we set as a conventional benchmark to ensure a high degree of reliability in the modeling of the explained variance between capillary and venous collection sites. Of these parameters, FC of HDL subfractions 3 and 4 demonstrated lower explained variance (Adj. R2 = 0.469, 0.486, respectively), however, the remaining 6 parameters (all from LDL subfraction 6, plus L2TG) demonstrated moderate explained variance (Adj. R2 range: 0.658–0.773), suggesting that their measurement in capillary samples is still a biologically valid alternative to traditional venous phlebotomy. It goes beyond the scope of this study to determine the exact mechanisms underlying the lower concentration predictability between collection sites, we postulate that these differences are attributed to sample handling and capillary sample dilution, (33) resulting in lower signal-to-noise ratios of parameters derived from smaller, denser subfractions. Considerations to improve sample handling include the use of high-flow lancets that mitigate squeezing of the fingertip, which can cause sample contamination with tissue fluid.
In serum samples, a minor difference was observed between collection sites in the low-frequency portion of SPC (SPC1), as observed from the respective spectra (Figure 2B). Previously, Masuda et al. identified that SPC1 is primarily characterized by the presence of HDL-4 and some HDL-3 phospholipid parameters. (40) In the present study, this aligns with the lower explained variance (i.e., Adj. R2 < 0.8) between collection sites in the serum lipoprotein assay for HDL-4 subfraction parameters, such as H4PL. Previously, Mallol et al. have reported that the time required for clot formation, which is critical in the collection of serum samples, necessitates attention to lipoprotein binding to the fibrin clot. (46) Importantly, this binding is more variable when samples are maintained at lower temperatures, such as 4 °C, in comparison to clotting occurring after a half-hour incubation at room temperature. (46) Since obtaining serum samples relies on the formation of a clot and capillary samples tend to exhibit increased levels of tissue factor that expedite the clotting process, (47) it is speculated that these distinctions in clotting dynamics may be implicated in the analysis of serum SPC1 and relevant parameters of the HDL-4 subfraction. The present study did not identify a similar phenomenon for plasma samples collected in lithium heparin (LH) anticoagulant tubes, indicating a stronger relationship in SPC1-related HDL-4 parameters between those in capillary and venous collections. These data emphasize the appropriate selection of blood tubes, particularly for studies investigating the parameters of SPC, where the selection of plasma over serum may mitigate blood clot-related lipoprotein differences in capillary samples.
The primary goal of the present study was to determine whether the analysis of capillary blood “microsamples” with low-volume 3 mm NMR workflows was representative of traditional venous samples. As a proof-of-concept, direct comparison to clinical measurements or ’ground truth’ was beyond the scope of this study. However, establishing a direct relationship with clinical measurements remains an important future direction. All 120 lipoprotein and inflammatory parameters measured in the present study, including concentration means and ranges for each collection site (capillary, venous) and biofluid (plasma, serum), are reported in Table S1.
Preliminary data from this study sheds light on the potential translatability for capillary blood microsample SPC and Glyc biomarker analysis, using a benchtop low-field 80 MHz benchtop NMR. While the JEDI-PGSE experiment demonstrated spectral overlay in both participants, emphasizing the robustness of SPC and Glyc measurements in plasma, variability was identified in the 1D experiment for participant one between the capillary and venous samples (Figure 4). It is noteworthy that small differences in sample collection methods between participants were observed, specifically─sampling under pressure (participant one) vs without (participant two)─with the former potentially influencing tissue fluid contamination during capillary microsampling. (33) Despite this variation, the preliminary data appear to underscore the overall resilience of SPC and Glyc measurements in capillary plasma, suggesting their potential reliability as biomarkers even under different sampling conditions. This preliminary insight into the potential impact of sample collection methods contributes valuable information, laying the foundation for future investigations and emphasizing the need for standardized protocols in capillary microsampling for accurate biomarker assessments.

Conclusions

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This research demonstrates equivalence between venous and capillary sampling for quantifying lipoproteins, supramolecular phospholipid composites (SPCs), and glycoproteins (Glycs), which has not been previously demonstrated for 3 mm NMR-based analytical workflows. This may confer a future diagnostic advantage over traditional venous phlebotomy methods since capillary blood microsampling can be performed longitudinally, at scale, and is suitable for community settings. This supports the extension of lipoprotein measurements, SPCs, and Glycs to remote areas and high-frequency sampling, presenting an opportunity for future translation to field-deployable benchtop instruments. Benchtop, low-field NMR spectrometers represent a cost-effective alternative for measurement of potential biomarkers at point-of-care. (18) Preliminary data from this study indicate that routine measurement of inflammatory SPC and Glyc biomarkers in plasma, using a field-deployable, benchtop 80 MHz NMR approach, could be achieved without the need for trained phlebotomists.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.analchem.3c05152.

  • B.I. LISA and PhenoRisk PACS RUO parameters and calculated concentrations (PDF)

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Author Information

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  • Corresponding Authors
    • Jeremy K. Nicholson - Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia;  Centre for Computational and Systems Medicine, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia;  Department of Cardiology, Fiona Stanley Hospital, Medical School, University of Western Australia, Murdoch, WA 6150, Australia;  Institute of Global Health Innovation, Faculty of Medicine, Imperial College London, Level 1, Faculty Building, South Kensington, London SW7 2NA, U.K.;  Orcidhttps://orcid.org/0000-0002-8123-8349;  Email: [email protected]
    • Julien Wist - Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia;  Centre for Computational and Systems Medicine, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia;  Faculty of Medicine, Department of Metabolism, Digestion and Reproduction, Division of Digestive Diseases, Imperial College, London SW7 2AZ, United Kingdom;  Chemistry Department, Universidad del Valle, Melendez 76001, Cali, Colombia;  Orcidhttps://orcid.org/0000-0002-3416-2572;  Email: [email protected]
    • Nathan G. Lawler - Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia;  Centre for Computational and Systems Medicine, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia;  Orcidhttps://orcid.org/0000-0001-9649-425X;  Email: [email protected]
  • Authors
    • Jayden Lee Roberts - Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia;  Centre for Computational and Systems Medicine, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia;  Orcidhttps://orcid.org/0000-0003-2236-2945
    • Luke Whiley - Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia;  Centre for Computational and Systems Medicine, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia;  Orcidhttps://orcid.org/0000-0002-9088-4799
    • Nicola Gray - Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia;  Centre for Computational and Systems Medicine, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia;  Orcidhttps://orcid.org/0000-0002-0094-5245
    • Melvin Gay - Bruker Pty Ltd., Preston, VIC 3072, Australia
    • Philipp Nitschke - Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia;  Centre for Computational and Systems Medicine, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia;  Orcidhttps://orcid.org/0000-0002-5814-7529
    • Reika Masuda - Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia;  Centre for Computational and Systems Medicine, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia
    • Elaine Holmes - Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia;  Centre for Computational and Systems Medicine, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Murdoch, WA 6150, Australia;  Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, South Kensington, London SW7 2AZ, U.K.;  Orcidhttps://orcid.org/0000-0002-0556-8389
  • Author Contributions

    J.L.R.: Writing, editing, conceptualization, and reviewing; N.G.L., L.W., N.G., and M.G.: Editing, reviewing, and conceptualization. P.N., R.M., E.H., and J.K.N.: Editing and reviewing. All authors have read and agreed to the published version of the manuscript.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This research was supported by a Joint Strategic Research Training Program Scholarship funded by Murdoch University and Bruker Daltonics to higher degree research students for J.L.R. E.H. acknowledges the H2020 EU GEMMA grant for funding. J.L.R. would like to acknowledge N.S.M.

Abbreviations

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°C

degrees Celcius
1H NMR

proton nuclear magnetic resonance spectroscopy
AB

apolipoprotein B100
ABA1

ratio between apolipoprotein B100 and apolipoprotein A1
B.I. LISA

Bruker IVDr lipoprotein subclass analysis
BBI

double resonance broadband probe
BD

Becton Dickinson
CAT

clot activation tube
CH

cholesterol
cm

centimeters
D2O

deuterium oxide
F80

Fourier 80
FC

free cholesterol
g

g-force
Glyc

glycoprotein
h

hours
H2O

water
HDL

high-density lipoprotein
IVDr

in vitro diagnostic research
JEDI

J-Edited DIffusional
k

thousand
kg

kilograms
LC

liquid chromatography
LDL

low-density lipoprotein
LH

lithium heparin
Lpa

lipoprotein a
MHz

megahertz
min

minutes
mL

milliliters
mm

millimeters
MS

mass spectrometry
N

number
P4 medicine

predictive, preventive, personalized, and participatory medicine
PGPE

pulsed gradient perfect echo
pH

potential of hydrogen
PL

phospholipids
PN

particle number
ppm

part per million
RUO

for research use only
SD

standard deviation
SE%

standard error percentage
SPC

supramolecular phospholipid composite
sw

spectral width
TC

total cholesterol
TG

triglycerides
TSP

sodium trimethylsilyl propionate-[2,2,3,3-2H4]
VLDL

very-low-density lipoprotein
WHO

World Health Organization
μL

microliters

References

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This article references 47 other publications.

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    We report an extensive 600 MHz NMR trial of quant. lipoprotein and small-mol. measurements in human blood serum and plasma. Five centers with eleven 600 MHz NMR spectrometers were used to analyze 98 samples including 20 quality controls (QCs), 37 com. sourced, paired serum and plasma samples, and two National Institute of Science and Technol. (NIST) ref. material 1951c replicates. Samples were analyzed using rigorous protocols for sample prepn. and exptl. acquisition. A com. lipoprotein subclass anal. was used to quantify 105 lipoprotein subclasses and 24 low mol. wt. metabolites from the NMR spectra. For all spectrometers, the instrument specific variance in measuring internal QCs was lower than the percentage described by the National Cholesterol Education Program (NCEP) criteria for lipid testing [triglycerides <2.7%; cholesterol <2.8%; low-d. lipoprotein (LDL) cholesterol <2.8%; high-d. lipoprotein (HDL) cholesterol <2.3%], showing exceptional reproducibility for direct quantitation of lipoproteins in both matrixes. The av. relative std. deviations (RSDs) for the 105 lipoprotein parameters in the 11 instruments were 4.6% and 3.9% for the two NIST samples, whereas they were 38% and 40% for the 37 com. sourced plasmas and sera, resp., showing negligible anal. compared to biol. variation. The coeff. of variance (CV) obtained for the quantification of the small mols. across the 11 spectrometers was below 15% for 20 out of the 24 metabolites analyzed. This study provides further evidence of the suitability of NMR for high-throughput lipoprotein subcomponent anal. and small-mol. quantitation with the exceptional required reproducibility for clin. and other regulatory settings.
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    Journal of Proteome Research (2021), 20 (2), 1415-1423CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)
    The utility of low sample vol. in vitro diagnostic (IVDr) proton NMR (1H NMR) spectroscopic expts. on blood plasma for information recovery from limited availability or high value samples was exemplified using plasma from patients with SARS-CoV-2 infection and normal controls. 1H NMR spectra were obtained using solvent-suppressed 1D, spin-echo (CPMG), and 2-dimensional J-resolved (JRES) spectroscopy using both 3 mm outer diam. SampleJet NMR tubes (100μL plasma) and 5 mm SampleJet NMR tubes (300μL plasma) under in vitro diagnostic conditions. We noted near identical diagnostic models in both std. and low vol. IVDr lipoprotein anal. (measuring 112 lipoprotein parameters) with a comparison of the two tubes yielding R2 values ranging between 0.82 and 0.99 for the 40 paired lipoprotein parameters samples. Lipoprotein measurements for the 3 mm tubes were achieved without time penalty over the 5 mm tubes as defined by biomarker recovery for SARS-CoV-2. Overall, biomarker pattern recovery for the lipoproteins was extremely similar, but there were some small pos. offsets in the linear equations for several variables due to small shimming artifacts, but there was minimal degrdn. of the biol. information. For the std. untargeted 1D, CPMG, and JRES NMR expts. on the same samples, the reduced signal-to-noise was more constraining and required greater scanning times to achieve similar differential diagnostic performance (15 min per sample per expt. for 3 mm 1D and CPMG, compared to 4 min for the 5 mm tubes). We conclude that the 3 mm IVDr method is fit-for-purpose for quant. lipoprotein measurements, allowing the prepn. of smaller vols. for high value or limited vol. samples that is common in clin. studies. If there are no anal. time constraints, the lower vol. expts. are equally informative for untargeted profiling.
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  13. 13
    Dona, A. C.; Jiménez, B.; Schäfer, H.; Humpfer, E.; Spraul, M.; Lewis, M. R.; Pearce, J. T. M.; Holmes, E.; Lindon, J. C.; Nicholson, J. K. Precision High-Throughput Proton NMR Spectroscopy of Human Urine, Serum, and Plasma for Large-Scale Metabolic Phenotyping. Anal. Chem. 2014, 86, 9887– 9894,  DOI: 10.1021/ac5025039
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    13
    Precision High-Throughput Proton NMR Spectroscopy of Human Urine, Serum, and Plasma for Large-Scale Metabolic Phenotyping
    Dona, Anthony C.; Jimenez, Beatriz; Schafer, Hartmut; Humpfer, Eberhard; Spraul, Manfred; Lewis, Matthew R.; Pearce, Jake T. M.; Holmes, Elaine; Lindon, John C.; Nicholson, Jeremy K.
    Analytical Chemistry (Washington, DC, United States) (2014), 86 (19), 9887-9894CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    Proton NMR-based metabolic phenotyping of urine and blood plasma/serum samples provides important prognostic and diagnostic information and permits monitoring of disease progression in an objective manner. Much effort has been made in recent years to develop NMR instrumentation and technol. to allow the acquisition of data in an effective, reproducible, and high-throughput approach that allows the study of general population samples from epidemiol. collections for biomarkers of disease risk. The challenge remains to develop highly reproducible methods and standardized protocols that minimize tech. or exptl. bias, allowing realistic interlab. comparisons of subtle biomarker information. Here the authors present a detailed set of updated protocols that carefully consider major exptl. conditions, including sample prepn., spectrometer parameters, NMR pulse sequences, throughput, reproducibility, quality control, and resoln. These results provide an exptl. platform that facilitates NMR spectroscopy usage across different large cohorts of biofluid samples, enabling integration of global metabolic profiling that is a prerequisite for personalized healthcare.
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  14. 14
    Otvos, J. D.; Shalaurova, I.; Wolak-Dinsmore, J.; Connelly, M. A.; Mackey, R. H.; Stein, J. H.; Tracy, R. P. GlycA: A Composite Nuclear Magnetic Resonance Biomarker of Systemic Inflammation. Clin. Chem. 2015, 61, 714– 723,  DOI: 10.1373/clinchem.2014.232918
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    14
    GlycA: a composite nuclear magnetic resonance biomarker of systemic inflammation
    Otvos, James D.; Shalaurova, Irina; Wolak-Dinsmore, Justyna; Connelly, Margery A.; Mackey, Rachel H.; Stein, James H.; Tracy, Russell P.
    Clinical Chemistry (Washington, DC, United States) (2015), 61 (5), 714-723CODEN: CLCHAU; ISSN:0009-9147. (American Association for Clinical Chemistry)
    NMR (NMR) spectra of serum obtained under quant. conditions for lipoprotein particle analyses contain addnl. signals that could potentially serve as useful clin. biomarkers. One of these signals that we named GlycA originates from a subset of glycan N-acetylglucosamine residues on enzymically glycosylated acute-phase proteins. We hypothesized that the amplitude of the GlycA signal might provide a unique and convenient measure of systemic inflammation. We developed a spectral deconvolution algorithm to quantify GlycA signal amplitudes from automated NMR LipoProfile test spectra and assessed analytic precision and biol. variability. Spectra of acute-phase glycoproteins and serum fractions were analyzed to probe the origins of the GlycA signal. GlycA concns. obtained from archived NMR LipoProfile spectra of baseline plasma from 5537 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) were used to assess assocns. with demog. and lab. parameters including measures of inflammation. Major acute-phase protein contributors to the serum GlycA signal are α1-acid glycoprotein, haptoglobin, α1-antitrypsin, α1-antichymotrypsin, and transferrin. GlycA concns. were correlated with high-sensitivity C-reactive protein (hsCRP) (r = 0.56), fibrinogen (r = 0.46), and interleukin-6 (IL-6) (r = 0.35) (all P < 0.0001). Analytic imprecision was low (intra- and interassay CVs 1.9% and 2.6%, resp.) and intraindividual variability, assessed weekly for 5 wk in 23 healthy volunteers, was 4.3%, lower than for hsCRP (29.2%), cholesterol (5.7%), and triglycerides (18.0%). GlycA is a unique inflammatory biomarker with analytic and clin. attributes that may complement or provide advantages over existing clin. markers of systemic inflammation.
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  15. 15
    Otvos, J. D.; Jeyarajah, E. J.; Bennett, D. W. Quantification of plasma lipoproteins by proton nuclear magnetic resonance spectroscopy. Clin. Chem. 1991, 37, 377– 386,  DOI: 10.1093/clinchem/37.3.377
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    15
    Quantification of plasma lipoproteins by proton nuclear magnetic resonance spectroscopy
    Otvos, J. D.; Jeyarajah, E. J.; Bennett, D. W.
    Clinical Chemistry (Washington, DC, United States) (1991), 37 (3), 377-86CODEN: CLCHAU; ISSN:0009-9147.
    A new anal. procedure for quantifying plasma lipoproteins by proton NMR spectroscopy has been developed that potentially offers significant advantages over existing clin. methods used for assessing risk of coronary heart disease. Anal. of a single spectrum of a nonfasting plasma sample, acquired simply and rapidly at moderate magnetic field strength (250 MHz), yields a complete profile of lipoprotein concns.: chylomicrons and very-low-, low-, and high-d. lipoproteins. The method is based on curve-fitting (spectral deconvolution) of the plasma Me lipid resonance envelope, the amplitude and shape of which depend directly on the amplitudes of the superimposed Me resonances of the lipoprotein components. A linear least-squares curve-fitting algorithm was developed to efficiently ext. the signal amplitudes (concns.) of the lipoproteins from the plasma spectrum. These signal amplitudes correlate well with lipoprotein concns. detd. by triglyceride and cholesterol measurements.
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  16. 16
    Ala-Korpela, M.; Korhonen, A.; Keisala, J.; Hörkkö, S.; Korpi, P.; Ingman, L. P.; Jokisaari, J.; Savolainen, M. J.; Kesäniemi, Y. A. 1H NMR-based absolute quantitation of human lipoproteins and their lipid contents directly from plasma. J. Lipid Res. 1994, 35, 2292– 2304,  DOI: 10.1016/S0022-2275(20)39935-1
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    16
    1H NMR-based absolute quantitation of human lipoproteins and their lipid contents directly from plasma
    Ala-Korpela, M.; Korhonen, A.; Keisala, J.; Hoerkkoe, S.; Korpi, P.; Ingman, L. P.; Jokisaari, J.; Savolainen, M. J.; Kesaeniemi, Y. A.
    Journal of Lipid Research (1994), 35 (12), 2292-304CODEN: JLPRAW; ISSN:0022-2275. (Lipid Research, Inc.)
    A new method is presented for abs. quantitation of lipid and protein contents of human lipoproteins directly from plasma. The method enables complete lipoprotein lipid profiles to be obtained in a total time of less than one hour. Abs. concns. of triglycerides, phospholipids, total cholesterol, free cholesterol, esterified cholesterol, total proteins, and total masses can be estd. for the very low d. (VLDL) and low d. (LDL) lipoprotein fractions. For the high d. lipoprotein (HDL) fraction all components except triglycerides can be quantitated. The method is a combination of 1H NMR spectroscopy and a sophisticated lineshape fitting anal. technique. In this paper we present the calibration of the method using 15 plasma samples followed by a double-blind test of 51 plasma samples from 43 individuals. In total, 66 plasma samples were analyzed. Comparison of the 1H NMR-based results with the data of the biochem. assays showed excellent agreement; the correlation coeff. for VLDL triglycerides was 0.98, for LDL cholesterol 0.88, and for HDL cholesterol 0.93. This method can be directly integrated to many kinds of biomedical NMR studies to offer addnl. biochem. important quant. lipoprotein information, the measurement of which is usually to laborious by conventional biochem. methods and too high-priced to be adapted into the study protocols. Moreover, the method also has considerable potential to be developed for a routine clin. assay.
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  17. 17
    Bell, J. D.; Brown, J. C. C.; Nicholson, J. K.; Sadler, P. J. Assignment of resonances for ‘acute-phase’ glycoproteins in high resolution proton NMR spectra of human blood plasma. FEBS Lett. 1987, 215, 311– 315,  DOI: 10.1016/0014-5793(87)80168-0
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    17
    Assignment of resonances for 'acute-phase' glycoproteins in high resolution proton NMR spectra of human blood plasma
    Bell, J. D.; Brown, J. C. C.; Nicholson, J. K.; Sadler, P. J.
    FEBS Letters (1987), 215 (2), 311-15CODEN: FEBLAL; ISSN:0014-5793.
    Broad resonances at 2.04 and 2.08 ppm in 500 MHz Hahn spin-echo 1H NMR spectra of human blood plasma are assigned to the N-acetyl groups of mobile carbohydrate side-chains (largely N-acetylglucosamine and N-acetylneuraminic acid) of glycoproteins such as α1-acid glycoprotein. Their intensities in spin-echo spectra correlate with clin. conditions in which an elevation of the level of acute-phase glycoproteins is expected, and so may be of value in the study of certain diseases.
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  18. 18
    Nitschke, P.; Lodge, S.; Hall, D.; Schaefer, H.; Spraul, M.; Embade, N.; Millet, O.; Holmes, E.; Wist, J.; Nicholson, J. K. Direct low field J-edited diffusional proton NMR spectroscopic measurement of COVID-19 inflammatory biomarkers in human serum. Analyst 2022, 147, 4213– 4221,  DOI: 10.1039/D2AN01097F
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    18
    Direct low field J-edited diffusional proton NMR spectroscopic measurement of COVID-19 inflammatory biomarkers in human serum
    Nitschke, Philipp; Lodge, Samantha; Hall, Drew; Schaefer, Hartmut; Spraul, Manfred; Embade, Nieves; Millet, Oscar; Holmes, Elaine; Wist, Julien; Nicholson, Jeremy K.
    Analyst (Cambridge, United Kingdom) (2022), 147 (19), 4213-4221CODEN: ANALAO; ISSN:0003-2654. (Royal Society of Chemistry)
    A JEDI NMR pulse expt. incorporating relaxational, diffusional and J-modulation peak editing has been implemented for a low field (80 MHz proton resonance frequency) spectrometer system to measure quant. two recently discovered plasma markers of SARS-CoV-2 infection and general inflammation. JEDI spectra capture a unique signature of two biomarker signals from acetylated glycoproteins (Glyc) and the supramol. phospholipid composite (SPC) signals that are relatively enhanced by the combination of relaxation, diffusion and J-editing properties of the JEDI expt. that strongly attenuate contributions from the other mol. species in plasma. The SPC/Glyc ratio data were essentially identical in the 600 MHz and 80 MHz spectra obtained (R2 = 0.97) and showed significantly different ratios for control (n = 28) vs. SARS-CoV-2 pos. patients (n = 29) (p = 5.2 x 10-8 and 3.7 x 10-8 resp.). Simplification of the sample prepn. allows for data acquisition in a similar time frame to high field machines (∼4 min) and a high-throughput version with 1 min expt. time could be feasible. These data show that these newly discovered inflammatory biomarkers can be measured effectively on low field NMR instruments that do not not require housing in a complex lab. environment, thus lowering the barrier to clin. translation of this diagnostic technol.
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  19. 19
    Lodge, S.; Nitschke, P.; Kimhofer, T.; Coudert, J. D.; Begum, S.; Bong, S.-H.; Richards, T.; Edgar, D.; Raby, E.; Spraul, M. NMR Spectroscopic Windows on the Systemic Effects of SARS-CoV-2 Infection on Plasma Lipoproteins and Metabolites in Relation to Circulating Cytokines. J. Proteome Res. 2021, 20, 1382– 1396,  DOI: 10.1021/acs.jproteome.0c00876
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    19
    NMR Spectroscopic Windows on the Systemic Effects of SARS-CoV-2 Infection on Plasma Lipoproteins and Metabolites in Relation to Circulating Cytokines
    Lodge, Samantha; Nitschke, Philipp; Kimhofer, Torben; Coudert, Jerome D.; Begum, Sofina; Bong, Sze-How; Richards, Toby; Edgar, Dale; Raby, Edward; Spraul, Manfred; Schaefer, Hartmut; Lindon, John C.; Loo, Ruey Leng; Holmes, Elaine; Nicholson, Jeremy K.
    Journal of Proteome Research (2021), 20 (2), 1382-1396CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)
    To investigate the systemic metabolic effects of SARS-CoV-2 infection, we analyzed 1H NMR spectroscopic data on human blood plasma and co-modeled with multiple plasma cytokines and chemokines (measured in parallel). Thus, 600 MHz 1H solvent-suppressed single-pulse, spin-echo, and 2D J-resolved spectra were collected on plasma recorded from SARS-CoV-2 rRT-PCR-pos. patients (n = 15, with multiple sampling timepoints) and age-matched healthy controls (n = 34, confirmed rRT-PCR neg.), together with patients with COVID-19/influenza-like clin. symptoms who tested SARS-CoV-2 neg. (n = 35). We compared the single-pulse NMR spectral data with in vitro diagnostic research (IVDr) information on quant. lipoprotein profiles (112 parameters) extd. from the raw 1D NMR data. All NMR methods gave highly significant discrimination of SARS-CoV-2 pos. patients from controls and SARS-CoV-2 neg. patients with individual NMR methods, giving different diagnostic information windows on disease-induced phenoconversion. Longitudinal trajectory anal. in selected patients indicated that metabolic recovery was incomplete in individuals without detectable virus in the recovery phase. We obsd. four plasma cytokine clusters that expressed complex differential statistical relationships with multiple lipoproteins and metabolites. These included the following: cluster 1, comprising MIP-1β, SDF-1α, IL-22, and IL-1α, which correlated with multiple increased LDL and VLDL subfractions; cluster 2, including IL-10 and IL-17A, which was only weakly linked to the lipoprotein profile; cluster 3, which included IL-8 and MCP-1 and were inversely correlated with multiple lipoproteins. IL-18, IL-6, and IFN-γ together with IP-10 and RANTES exhibited strong pos. correlations with LDL1-4 subfractions and neg. correlations with multiple HDL subfractions. Collectively, these data show a distinct pattern indicative of a multilevel cellular immune response to SARS CoV-2 infection interacting with the plasma lipoproteome giving a strong and characteristic immunometabolic phenotype of the disease. We obsd. that some patients in the respiratory recovery phase and testing virus-free were still metabolically highly abnormal, which indicates a new role for these technologies in assessing full systemic recovery.
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  20. 20
    Walldius, G.; Jungner, I.; Holme, I.; Aastveit, A. H.; Kolar, W.; Steiner, E. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet 2001, 358, 2026– 2033,  DOI: 10.1016/S0140-6736(01)07098-2
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    20
    High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study
    Walldius, Goran; Jungner, Ingmar; Holme, Ingar; Aastveit, Are H.; Kolar, Werner; Steiner, Eugen
    Lancet (2001), 358 (9298), 2026-2033CODEN: LANCAO; ISSN:0140-6736. (Lancet Ltd.)
    Background: Apolipoprotein B (apoB) and apolipoprotein A-I (apoA-I) are thought to be better predictors of acute myocardial infarction than total cholesterol and LDL-cholesterol. We investigated whether apoB and apoA-I are predictors of risk of fatal myocardial infarction. We also aimed to establish whether apoB and apoA-I add further information about risk of fatal myocardial infarction to that obtained with total cholesterol, triglycerides, and LDL-cholesterol. Methods: We recruited 175553 individuals mainly from screening programs. We measured concns. of apoB, apoA-I, total cholesterol, and triglycerides, and calcd. apoB/apoA-I ratio and concns. of LDL-cholesterol and HDL-cholesterol. The relation between death from acute myocardial infarction and initial values for apoB, apoA-I, and the other lipids was examd. Findings: Mean follow-up was 66·8 mo (SD 41·3) for 98722 men and 64·4 mo (41·4) for 76831 women. 864 Men and 359 women had fatal myocardial infarction. In univariate analyses adjusted for age and in multivariate analyses adjusted for age, total cholesterol, and triglycerides, the values for apoB and apoB/apoA-I ratio were strongly and pos. related to increased risk of fatal myocardial infarction in men and in women. ApoA-I was noted to be protective. In multivariate anal., apoB was a stronger predictor of risk than LDL-cholesterol in both sexes. Interpretation: Although LDL-cholesterol and HDL-cholesterol are known risk factors, we suggest that apoB, apoB/apoA-I, and apoA-I should also be regarded as highly predictive in evaluation of cardiac risk. Although increased throughout the range of values of LDL-cholesterol, apoB and apoA-I might be of greatest value in diagnosis and treatment in men and women who have common lipid abnormalities, but have normal or low concns. of LDL-cholesterol.
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  21. 21
    Walldius, G. The apoB/apoA-I Ratio is a Strong Predictor of Cardiovascular Risk. In Lipoproteins; Sasa, F.; Gerhard, K., Eds.; IntechOpen, 2012, Chapter 5.
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    There is no corresponding record for this reference.
  22. 22
    Rössler, T.; Berezhnoy, G.; Singh, Y.; Cannet, C.; Reinsperger, T.; Schäfer, H.; Spraul, M.; Kneilling, M.; Merle, U.; Trautwein, C. Quantitative Serum NMR Spectroscopy Stratifies COVID-19 Patients and Sheds Light on Interfaces of Host Metabolism and the Immune Response with Cytokines and Clinical Parameters. Metabolites 2022, 12, 1277  DOI: 10.3390/metabo12121277
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    There is no corresponding record for this reference.
  23. 23
    Kazenwadel, J.; Berezhnoy, G.; Cannet, C.; Schäfer, H.; Geisler, T.; Rohlfing, A.-K.; Gawaz, M.; Merle, U.; Trautwein, C. Stratification of hypertension and SARS-CoV-2 infection by quantitative NMR spectroscopy of human blood serum. Commun. Med. 2023, 3, 145,  DOI: 10.1038/s43856-023-00365-y
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    23
    Stratification of hypertension and SARS-CoV-2 infection by quantitative NMR spectroscopy of human blood serum
    Kazenwadel, Jasmin; Berezhnoy, Georgy; Cannet, Claire; Schaefer, Hartmut; Geisler, Tobias; Rohlfing, Anne-Katrin; Gawaz, Meinrad; Merle, Uta; Trautwein, Christoph
    Communications Medicine (2023), 3 (1), 145CODEN: CMOECM; ISSN:2730-664X. (Nature Portfolio)
    Abstr.: Background: Diagnostic approaches like the NMR spectroscopy (NMR) based quantification of metabolites, lipoproteins, and inflammation markers has helped to identify typical alterations in the blood serum of COVID-19 patients. However, confounders such as sex, and comorbidities, which strongly influence the metabolome, were often not considered. Therefore, the aim of this NMR study was to consider sex, as well as arterial hypertension (AHT), when investigating COVID-19-pos. serum samples in a large age-and sex matched cohort. Methods: NMR serum data from 329 COVID-19 patients were compared with 305 healthy controls. 134 COVID-19 patients were affected by AHT. These were analyzed together with NMR data from 58 hypertensives without COVID-19. In addn. to metabolite, lipoprotein, and glycoprotein data from NMR, common lab. parameters were considered. Sex was considered in detail for all comparisons. Results: Here, we show that several differences emerge from previous NMR COVID-19 studies when AHT is considered. Esp., the previously described triglyceride-rich lipoprotein profile is no longer obsd. in COVID-19 patients, nor an increase in ketone bodies. Further alterations are a decrease in glutamine, leucine, isoleucine, and lysine, citric acid, HDL-4 particles, and total cholesterol. Addnl., hypertensive COVID-19 patients show higher inflammatory NMR parameters than normotensive patients. Conclusions: We present a more precise picture of COVID-19 blood serum parameters. Accordingly, considering sex and comorbidities should be included in future metabolomics studies for improved and refined patient stratification. Due to metabolic similarities with other viral infections, these results can be applied to other respiratory diseases in the future.
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  24. 24
    Masuda, R.; Lodge, S.; Whiley, L.; Gray, N.; Lawler, N.; Nitschke, P.; Bong, S.-H.; Kimhofer, T.; Loo, R. L.; Boughton, B.; Zeng, A. X.; Hall, D.; Schaefer, H.; Spraul, M.; Dwivedi, G.; Yeap, B. B.; Diercks, T.; Bernardo-Seisdedos, G.; Mato, J. M.; Lindon, J. C.; Holmes, E.; Millet, O.; Wist, J.; Nicholson, J. K. Exploration of Human Serum Lipoprotein Supramolecular Phospholipids Using Statistical Heterospectroscopy in n-Dimensions (SHY-n): Identification of Potential Cardiovascular Risk Biomarkers Related to SARS-CoV-2 Infection. Anal. Chem. 2022, 94, 4426– 4436,  DOI: 10.1021/acs.analchem.1c05389
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    47
    Exploration of Human Serum Lipoprotein Supramolecular Phospholipids Using Statistical Heterospectroscopy in n-Dimensions (SHY-n): Identification of Potential Cardiovascular Risk Biomarkers Related to SARS-CoV-2 Infection
    Masuda, Reika; Lodge, Samantha; Whiley, Luke; Gray, Nicola; Lawler, Nathan; Nitschke, Philipp; Bong, Sze-How; Kimhofer, Torben; Loo, Ruey Leng; Boughton, Berin; Zeng, Annie X.; Hall, Drew; Schaefer, Hartmut; Spraul, Manfred; Dwivedi, Girish; Yeap, Bu B.; Diercks, Tammo; Bernardo-Seisdedos, Ganeko; Mato, Jose M.; Lindon, John C.; Holmes, Elaine; Millet, Oscar; Wist, Julien; Nicholson, Jeremy K.
    Analytical Chemistry (Washington, DC, United States) (2022), 94 (10), 4426-4436CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    SARS-CoV-2 infection causes a significant redn. in lipoprotein-bound serum phospholipids give rise to supramol. phospholipid composite (SPC) signals obsd. in diffusion and relaxation edited 1H NMR spectra. 17708906. To characterize the chem. structural components and compartmental location of SPC and to understand further its possible diagnostic properties, we applied a Statistical HeterospectroscopY in n-dimensions (SHY-n) approach. This involved statistically linking a series of orthogonal measurements made on the same samples, using independent anal. techniques and instruments, to identify the major individual phospholipid components giving rise to the SPC signals. Thus, an integrated model for SARS-CoV-2 pos. and control adults is presented that relates three identified diagnostic subregions of the SPC signal envelope (SPC1, SPC2, and SPC3) generated using diffusion and relaxation edited (DIRE) NMR spectroscopy to lipoprotein and lipid measurements obtained by in vitro diagnostic NMR spectroscopy and ultrahigh-performance liq. chromatog.-tandem mass spectrometry (UHPLC-MS/MS). The SPC signals were then correlated sequentially with (a) total phospholipids in lipoprotein subfractions; (b) apolipoproteins B100, A1, and A2 in different lipoproteins and subcompartments; and (c) MS-measured total serum phosphatidylcholines present in the NMR detection range (i.e., PCs: 16.0,18.2; 18.0,18.1; 18.2,18.2; 16.0,18.1; 16.0,20.4; 18.0,18.2; 18.1,18.2), lysophosphatidylcholines (LPCs: 16.0 and 18.2), and sphingomyelin (SM 22.1). The SPC3/SPC2 ratio correlated strongly (r = 0.86) with the apolipoprotein B100/A1 ratio, a well-established marker of cardiovascular disease risk that is markedly elevated during acute SARS-CoV-2 infection. These data indicate the considerable potential of using a serum SPC measurement as a metric of cardiovascular risk based on a single NMR expt. This is of specific interest in relation to understanding the potential for increased cardiovascular risk in COVID-19 patients and risk persistence in post-acute COVID-19 syndrome (PACS).
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  25. 25
    Mallagaray, A.; Rudolph, L.; Lindloge, M.; Molbitz, J.; Thomsen, H.; Schmelter, F.; Alhabash, M. W.; Abdullah, M. R.; Saraei, R.; Ehlers, M.; Graf, T.; Sina, C.; Petersmann, A.; Nauck, M.; Gunther, U. L. Towards a Precise NMR Quantification of Acute Phase Inflammation Proteins from Human Serum. Angew. Chem. 2023, 62, e202306154  DOI: 10.1002/anie.202306154
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    24
    Towards a Precise NMR Quantification of Acute Phase Inflammation Proteins from Human Serum
    Mallagaray, Alvaro; Rudolph, Lorena; Lindloge, Melissa; Molbitz, Jarne; Thomsen, Henrik; Schmelter, Franziska; Alhabash, Mohamad Ward; Abdullah, Mohammed R.; Saraei, Roza; Ehlers, Marc; Graf, Tobias; Sina, Christian; Petersmann, Astrid; Nauck, Matthias; Guenther, Ulrich L.
    Angewandte Chemie, International Edition (2023), 62 (35), e202306154CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    NMR (NMR) spectra of human serum and plasma show, besides metabolites and lipoproteins, two characteristic signals termed GlycA and B arising from the acetyl groups of glycoprotein glycans from acute phase proteins, which constitute good markers for inflammatory processes. Here, we report a comprehensive assignment of glycoprotein glycan NMR signals obsd. in human serum, showing that GlycA and GlycB signals originate from Neu5Ac and GlcNAc moieties from N-glycans, resp. Diffusion-edited NMR expts. demonstrate that signal components can be assocd. with specific acute phase proteins. Conventionally detd. concns. of acute phase glycoproteins correlate well with distinct features in NMR spectra (R2 up to 0.9422, p-value <0.001), allowing the simultaneous quantification of several acute phase inflammation proteins. Overall, a proteo-metabolomics NMR signature of significant diagnostic potential is obtained within 10-20 min acquisition time. This is exemplified in serum samples from COVID-19 and cardiogenic shock patients showing significant changes in several acute phase proteins compared to healthy controls.
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  26. 26
    Anderson, N. L.; Anderson, N. G. The human plasma proteome: history, character, and diagnostic prospects. Mol. Cell. Proteomics 2002, 1, 845– 867,  DOI: 10.1074/mcp.R200007-MCP200
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    The human plasma proteome. History, character, and diagnostic prospects
    Anderson, N. Leigh; Anderson, Norman G.
    Molecular and Cellular Proteomics (2002), 1 (11), 845-867CODEN: MCPOBS; ISSN:1535-9476. (American Society for Biochemistry and Molecular Biology, Inc.)
    A review. The human plasma proteome holds the promise of a revolution in disease diagnosis and therapeutic monitoring provided that major challenges in proteomics and related disciplines can be addressed. Plasma is not only the primary clin. specimen but also represents the largest and deepest version of the human proteome present in any sample: in addn. to the classical "plasma proteins," it contains all tissue proteins (as leakage markers) plus very numerous distinct Ig sequences, and it has an extraordinary dynamic range in that more than 10 orders of magnitude in concn. sep. albumin and the rarest proteins now measured clin. Although the restricted dynamic range of conventional proteomic technol. (two-dimensional gels and mass spectrometry) has limited its contribution to the list of 289 proteins (tabulated here) that have been reported in plasma to date, very recent advances in multidimensional survey techniques promise at least double this no. in the near future. Abundant scientific evidence, from proteomics and other disciplines, suggests that among these are proteins whose abundances and structures change in ways indicative of many, if not most, human diseases. Nevertheless, only a handful of proteins are currently used in routine clin. diagnosis, and the rate of introduction of new protein tests approved by the United States Food and Drug Administration (FDA) has paradoxically declined over the last decade to less than one new protein diagnostic marker per yr. We speculate on the reasons behind this large discrepancy between the expectations arising from proteomics and the realities of clin. diagnostics and suggest approaches by which protein-disease assocns. may be more effectively translated into diagnostic tools in the future.
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  27. 27
    Yu, Z.; Kastenmüller, G.; He, Y.; Belcredi, P.; Möller, G.; Prehn, C.; Mendes, J.; Wahl, S.; Roemisch-Margl, W.; Ceglarek, U. Differences between Human Plasma and Serum Metabolite Profiles. PLoS One 2011, 6, e21230  DOI: 10.1371/journal.pone.0021230
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    Differences between human plasma and serum metabolite profiles
    Yu, Zhonghao; Kastenmueller, Gabi; He, Ying; Belcredi, Petra; Moeller, Gabriele; Prehn, Cornelia; Mendes, Joaquim; Wahl, Simone; Roemisch-Margl, Werner; Ceglarek, Uta; Polonikov, Alexey; Dahmen, Norbert; Prokisch, Holger; Xie, Lu; Li, Yixue; Wichmann, H.-Erich; Peters, Annette; Kronenberg, Florian; Suhre, Karsten; Adamski, Jerzy; Illig, Thomas; Wang-Sattler, Rui
    PLoS One (2011), 6 (7), e21230CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    Background: Human plasma and serum are widely used matrixes in clin. and biol. studies. However, different collecting procedures and the coagulation cascade influence concns. of both proteins and metabolites in these matrixes. The effects on metabolite concn. profiles have not been fully characterized. Methodol./Principal Findings: We analyzed the concns. of 163 metabolites in plasma and serum samples collected simultaneously from 377 fasting individuals. To ensure data quality, 41 metabolites with low measurement stability were excluded from further anal. In addn., plasma and corresponding serum samples from 83 individuals were re-measured in the same plates and mean correlation coeffs. (r) of all metabolites between the duplicates were 0.83 and 0.80 in plasma and serum, resp., indicating significantly better stability of plasma compared to serum (p = 0.01). Metabolite profiles from plasma and serum were clearly distinct with 104 metabolites showing significantly higher concns. in serum. In particular, 9 metabolites showed relative concn. differences larger than 20%. Despite differences in abs. concn. between the two matrixes, for most metabolites the overall correlation was high (mean r = 0.81 ± 0.10), which reflects a proportional change in concn. Furthermore, when two groups of individuals with different phenotypes were compared with each other using both matrixes, more metabolites with significantly different concns. could be identified in serum than in plasma. For example, when 51 type 2 diabetes (T2D) patients were compared with 326 non-T2D individuals, 15 more significantly different metabolites were found in serum, in addn. to the 25 common to both matrixes. Conclusions/Significance: Our study shows that reproducibility was good in both plasma and serum, and better in plasma. Furthermore, as long as the same blood prepn. procedure is used, either matrix should generate similar results in clin. and biol. studies. The higher metabolite concns. in serum, however, make it possible to provide more sensitive results in biomarker detection.
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    Leeman, M.; Choi, J.; Hansson, S.; Storm, M. U.; Nilsson, L. Proteins and antibodies in serum, plasma, and whole blood-size characterization using asymmetrical flow field-flow fractionation (AF4). Anal. Bioanal. Chem. 2018, 410, 4867– 4873,  DOI: 10.1007/s00216-018-1127-2
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    27
    Proteins and antibodies in serum, plasma, and whole blood-size characterization using asymmetrical flow field-flow fractionation (AF4)
    Leeman, Mats; Choi, Jaeyeong; Hansson, Sebastian; Storm, Matilda Ulmius; Nilsson, Lars
    Analytical and Bioanalytical Chemistry (2018), 410 (20), 4867-4873CODEN: ABCNBP; ISSN:1618-2642. (Springer)
    The anal. of aggregates of therapeutic proteins is crucial to ensure efficacy and patient safety. Typically, the anal. was performed in the finished formulation to ensure that aggregates are not present. An important question is, however, what happens to therapeutic proteins, with regard to oligomerization and aggregation, after they have been administered (i.e., in the blood). The sepn. of whole blood, plasma, and serum is shown using asym. flow field-flow fractionation (AF4) with a min. of sample pre-treatment. Furthermore, the anal. and size characterization of a fluorescent antibody in blood plasma using AF4 are demonstrated. The results show the suitability and strength of AF4 for blood anal. and open new important routes for the anal. and characterization of therapeutic proteins in the blood.
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    Collins, L. A.; Olivier, M. Quantitative comparison of lipoprotein fractions derived from human plasma and serum by liquid chromatography-tandem mass spectrometry. Proteome Sci. 2010, 8, 42,  DOI: 10.1186/1477-5956-8-42
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    28
    Quantitative comparison of lipoprotein fractions derived from human plasma and serum by liquid chromatography-tandem mass spectrometry
    Collins Lisamarie A; Olivier Michael
    Proteome science (2010), 8 (), 42 ISSN:.
    BACKGROUND: Lipoproteins are complex, globular molecules which play essential roles in the transport and metabolism of cholesterol. Their implication in the development of cardiovascular diseases, such as atherosclerosis, has sustained a great deal of interest in these particles. Their various functions, and their contribution to the development of atherosclerosis, are often attributed to their protein constituents, which vary greatly among the different lipoprotein classes. Recent advances in the field of mass spectrometry have provided insight into the array of proteins associated with low-density lipoproteins (LDLs) and, even more so, with high-density lipoproteins (HDLs). Plasma and serum are the most commonly used samples for the analysis of lipoproteins. Although these lipoprotein sources are unique, it was our goal to determine whether or not their inherent differences would ultimately affect a quantitative analysis of the LDL and HDL proteomes. To this end, we isolated LDL and HDL fractions with fast protein liquid chromatography-size exclusion chromatography (FPLC-SEC) from both human plasma and serum samples from the same individuals. After delipidating these samples, we performed a quantitative proteomic analysis to compare the lipoprotein-associated proteins derived from both plasma and serum. RESULTS: Although the primary differences between the samples are found in fibrinogen proteins which are removed from serum, it of interest to note that, with respect to LDL-associated proteins, apolipoproteinB-100 was found at significantly higher levels in serum samples. Complement component 3 was found at significantly higher levels in serum-derived HDL fractions. Both of these proteins are known LDL- and HDL-associated proteins, respectively. CONCLUSION: Overall, the results from our study indicate that both plasma and serum samples are equally suited for proteomic studies, and provide similar results. These findings are particularly important for studies profiling proteomic differences in lipoprotein particle composition in a variety of disease conditions, including cardiovascular disease.
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    Lippi, G.; Giampaolo, L.; Guidi, G. Effects of anticoagulants on lipoprotein(a) measurements with four commercial assays. Eur. J. Clin. Chem. Clin. Biochem. 1996, 34, 251– 255,  DOI: 10.1515/cclm.1996.34.3.251
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    Effects of anticoagulants on lipoprotein(a) measurements with four commercial assays
    Lippi, Giuseppe; Giampaolo, Lidia; Guidi, Giancesare
    European Journal of Clinical Chemistry and Clinical Biochemistry (1996), 34 (3), 251-5CODEN: EJCBEO; ISSN:0939-4974. (de Gruyter)
    Lipoprotein(a) (Lp(a)) levels in plasma are considered an independent risk factor for atherosclerosis at different sites. Although Lp(a) measurements have recently gained interest in clin. labs., several problems are still unresolved. A potential source of pre-anal. variability lies in the treatment of the specimens, since it has been reported that values of several lipid quantities are lower when measured in plasma instead of serum. Lp(a) was measured in serum and in EDTA-treated, heparinized and citrated plasma from 15 healthy volunteers. Four anal. methods were used: two enzyme linked immunosorbent assays [ELISA] based on a polyclonal antiapolipoprotein(a) antibody and a polyclonal anti-apolipoprotein B antibody, resp.; and two immunonephelometric assays [INA] based on a N antiserum to Lp(a) and on three monoclonal antibodies adsorbed on latex particles, resp. The measured Lp(a) values in plasma were lower than those found in serum, in particular for EDTA-treated (anti-apolipoprotein(a) ELISA: p < 0.01, anti-apolipoprotein B ELISA: p < 0.001 and Latex enhanced INA: p < 0.001) and citrated plasma (anti-apolipoprotein(a) ELISA: p < 0.05, anti-apolipoprotein B ELISA: p < 0.001 and INA: p < 0.001). Lp(a) values measured in heparinized plasma were also lower than those found in serum, but the difference was not statistically significant.
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  31. 31
    Loo, R. L.; Lodge, S.; Kimhofer, T.; Bong, S.-H.; Begum, S.; Whiley, L.; Gray, N.; Lindon, J. C.; Nitschke, P.; Lawler, N. G. Quantitative In-Vitro Diagnostic NMR Spectroscopy for Lipoprotein and Metabolite Measurements in Plasma and Serum: Recommendations for Analytical Artifact Minimization with Special Reference to COVID-19/SARS-CoV-2 Samples. J. Proteome Res. 2020, 19, 4428– 4441,  DOI: 10.1021/acs.jproteome.0c00537
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    30
    Quantitative In-Vitro Diagnostic NMR Spectroscopy for Lipoprotein and Metabolite Measurements in Plasma and Serum: Recommendations for Analytical Artifact Minimization with Special Reference to COVID-19/SARS-CoV-2 Samples
    Loo, Ruey Leng; Lodge, Samantha; Kimhofer, Torben; Bong, Sze-How; Begum, Sofina; Whiley, Luke; Gray, Nicola; Lindon, John C.; Nitschke, Philipp; Lawler, Nathan G.; Schafer, Hartmut; Spraul, Manfred; Richards, Toby; Nicholson, Jeremy K.; Holmes, Elaine
    Journal of Proteome Research (2020), 19 (11), 4428-4441CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)
    Quant. NMR (NMR) spectroscopy of blood plasma is widely used to investigate perturbed metabolic processes in human diseases. The reliability of biochem. data derived from these measurements is dependent on the quality of the sample collection and exact prepn. and anal. protocols. Here, we describe systematically, the impact of variations in sample collection and prepn. on information recovery from quant. proton (1H) NMR spectroscopy of human blood plasma and serum. The effects of variation of blood collection tube sizes and preservatives, successive freeze-thaw cycles, sample storage at -80°C, and short-term storage at 4 and 20°C on the quant. lipoprotein and metabolite patterns were investigated. Storage of plasma samples at 4°C for up to 48 h, freezing at -80°C and blood sample collection tube choice have few and minor effects on quant. lipoprotein profiles, and even storage at 4°C for up to 168 h caused little information loss. In contrast, the impact of heat-treatment (56°C for 30 min), which has been used for inactivation of SARS-CoV-2 and other viruses, that may be required prior to anal. measurements in low level biosecurity facilities induced marked changes in both lipoprotein and low mol. wt. metabolite profiles. It was conclusively demonstrated that this heat inactivation procedure degrades lipoproteins and changes metabolic information in complex ways. Plasma from control individuals and SARS-CoV-2 infected patients are differentially altered resulting in the creation of artifactual pseudo-biomarkers and destruction of real biomarkers to the extent that data from heat-treated samples are largely uninterpretable. We also present several simple blood sample handling recommendations for optimal NMR-based biomarker discovery investigations in SARS CoV-2 studies and general clin. biomarker research.
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    Vignoli, A.; Tenori, L.; Morsiani, C.; Turano, P.; Capri, M.; Luchinat, C. Serum or Plasma (and Which Plasma), That Is the Question. J. Proteome Res. 2022, 21, 1061– 1072,  DOI: 10.1021/acs.jproteome.1c00935
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    31
    Serum or Plasma (and Which Plasma), That Is the Question
    Vignoli, Alessia; Tenori, Leonardo; Morsiani, Cristina; Turano, Paola; Capri, Miriam; Luchinat, Claudio
    Journal of Proteome Research (2022), 21 (4), 1061-1072CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)
    Blood derivs. are the biofluids of choice for metabolomic clin. studies since blood can be collected with low invasiveness and is rich in biol. information. However, the choice of the blood collection tubes has an undeniable impact on the plasma and serum metabolic content. Here, we compared the metabolomic and lipoprotein profiles of blood samples collected at the same time and place from six healthy volunteers but using different collection tubes (each enrolled volunteer provided multiple blood samples at a distance of a few weeks/mo): citrate plasma, EDTA plasma, and serum tubes. All samples were analyzed via NMR spectroscopy. Several metabolites showed statistically significant alterations among the three blood matrixes, and also metabolites' correlations were shown to be affected. The effects of blood collection tubes on the lipoproteins' profiles are relevant too, but less marked. Overcoming the issue assocd. with different blood collection tubes is pivotal to scale metabolomics and lipoprotein anal. at the level of epidemiol. studies based on samples from multicenter cohorts. We propose a statistical soln., based on regression, that is shown to be efficient in reducing the alterations induced by the different collection tubes for both the metabolomic and lipoprotein profiles.
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    Capillary Sampling – Guidelines on Drawing Blood: Best Practices in Phlebotomy WHO: 2010.
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    Kupke, I. R.; Zeugner, S.; Gottschalk, A.; Kather, B. Differences in lipid and lipoprotein concentrations of capillary and venous blood samples. Clin. Chim. Acta 1979, 97, 279– 283,  DOI: 10.1016/0009-8981(79)90426-1
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    Differences in lipid and lipoprotein concentrations of capillary and venous blood samples
    Kupke, I. R.; Zeugner, S.; Gottschalk, A.; Kather, B.
    Clinica Chimica Acta (1979), 97 (2-3), 279-83CODEN: CCATAR; ISSN:0009-8981.
    The concns. of lipids and lipoproteins measured in capillary blood serum taken from young adults were significantly lower than in venous blood, although they correlated satisfactorily. These differences may reflect differences in the morphol. and hemodynamic conditions existing either in large veins or in the peripheral circulatory system. Thus, venous and capillary blood serum cannot be used interchangeably for these estns.
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    Kupke, I. R.; Kather, B.; Zeugner, S. On the composition of capillary and venous blood serum. Clin. Chim. Acta 1981, 112, 177– 185,  DOI: 10.1016/0009-8981(81)90376-4
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    On the composition of capillary and venous blood serum
    Kupke, I. R.; Kather, B.; Zeugner, S.
    Clinica Chimica Acta (1981), 112 (2), 177-85CODEN: CCATAR; ISSN:0009-8981.
    The concns. of various clin.-chem. substances in the capillary and venous blood serum of apparently healthy adults (20-30 yr) were examd. in the fasting state. Total protein, bilirubin, Ca, Na, and C- concns. were significantly lower in capillary than in venous serum. In nonhemolytic capillary serums, the concn. of K was nearly the same as in venous samples. Inorg. P and urea concns. were identical in both specimens. There was a tendency for glucose concns. to be higher in capillary than in venous serum. Capillary and venous blood serum can be used interchangeably only for certain purposes. These results are valid for apparently healthy adults in the fasting state; other population samples remain to be investigated.
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    Sedgwick, M. J.; Morris, J. G.; Nevill, M. E.; Barrett, L. A. Comparison of lipid and lipoprotein concentrations obtained when using capillary and venous plasma. Atherosclerosis 2011, 218, e10  DOI: 10.1016/j.atherosclerosis.2011.07.085
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    Lodge, S.; Nitschke, P.; Kimhofer, T.; Wist, J.; Bong, S.-H.; Loo, R. L.; Masuda, R.; Begum, S.; Richards, T.; Lindon, J. C. Diffusion and Relaxation Edited Proton NMR Spectroscopy of Plasma Reveals a High-Fidelity Supramolecular Biomarker Signature of SARS-CoV-2 Infection. Anal. Chem. 2021, 93, 3976– 3986,  DOI: 10.1021/acs.analchem.0c04952
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    36
    Diffusion and Relaxation Edited Proton NMR Spectroscopy of Plasma Reveals a High-Fidelity Supramolecular Biomarker Signature of SARS-CoV-2 Infection
    Lodge, Samantha; Nitschke, Philipp; Kimhofer, Torben; Wist, Julien; Bong, Sze-How; Loo, Ruey Leng; Masuda, Reika; Begum, Sofina; Richards, Toby; Lindon, John C.; Bermel, Wolfgang; Reinsperger, Tony; Schaefer, Hartmut; Spraul, Manfred; Holmes, Elaine; Nicholson, Jeremy K.
    Analytical Chemistry (Washington, DC, United States) (2021), 93 (8), 3976-3986CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    We have applied NMR spectroscopy based plasma phenotyping to reveal diagnostic mol. signatures of SARS-CoV-2 infection via combined diffusional and relaxation editing (DIRE). We compared plasma from healthy age-matched controls (n = 26) with SARS-CoV-2 neg. non-hospitalized respiratory patients and hospitalized respiratory patients (n = 23 and 11 resp.) with SARS-CoV-2 rRT-PCR pos. respiratory patients (n = 17, with longitudinal sampling time-points). DIRE data were modelled using principal component anal. and orthogonal projections to latent structures discriminant anal. (O-PLS-DA), with statistical cross-validation indexes indicating excellent model generalization for the classification of SARS-CoV-2 positivity for all comparator groups (area under the receiver operator characteristic curve = 1). DIRE spectra show biomarker signal combinations conferred by differential concns. of metabolites with selected mol. mobility properties. These comprise the following: (a) composite N-acetyl signals from α-1-acid glycoprotein and other glycoproteins (designated GlycA and GlycB) that were elevated in SARS-CoV-2 pos. patients [p = 2.52 x 10-10 (GlycA) and 1.25 x 10-9 (GlycB) vs controls], (b) two diagnostic supramol. phospholipid composite signals that were identified (SPC-A and SPC-B) from the -+N-(CH3)3 choline headgroups of lysophosphatidylcholines carried on plasma glycoproteins and from phospholipids in high-d. lipoprotein subfractions (SPC-A) together with a phospholipid component of low-d. lipoprotein (SPC-B). The integrals of the summed SPC signals (SPCtotal) were reduced in SARS-CoV-2 pos. patients relative to both controls (p = 1.40 x 10-7) and SARS-CoV-2 neg. patients (p = 4.52 x 10-8) but were not significantly different between controls and SARS-CoV-2 neg. patients. The identity of the SPC signal components was detd. using one and two dimensional diffusional, relaxation, and statistical spectroscopic expts. The SPCtotal/GlycA ratios were also significantly different for control vs. SARS-CoV-2 pos. patients (p = 1.23 x 10-10) and for SARS-CoV-2 negatives vs. positives (p = 1.60 x 10-9). Thus, plasma SPCtotal and SPCtotal/GlycA are proposed as sensitive mol. markers for SARS-CoV-2 positivity that could effectively augment current COVID-19 diagnostics and may have value in functional assessment of the disease recovery process in patients with long-term symptoms.
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    Kimhofer, T.; Lodge, S.; Whiley, L.; Gray, N.; Loo, R. L.; Lawler, N. G.; Nitschke, P.; Bong, S.-H.; Morrison, D. L.; Begum, S. Integrative Modeling of Quantitative Plasma Lipoprotein, Metabolic, and Amino Acid Data Reveals a Multiorgan Pathological Signature of SARS-CoV-2 Infection. J. Proteome Res. 2020, 19, 4442– 4454,  DOI: 10.1021/acs.jproteome.0c00519
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    Integrative Modeling of Quantitative Plasma Lipoprotein, Metabolic, and Amino Acid Data Reveals a Multiorgan Pathological Signature of SARS-CoV-2 Infection
    Kimhofer, Torben; Lodge, Samantha; Whiley, Luke; Gray, Nicola; Loo, Ruey Leng; Lawler, Nathan G.; Nitschke, Philipp; Bong, Sze-How; Morrison, David L.; Begum, Sofina; Richards, Toby; Yeap, Bu B.; Smith, Chris; Smith, Kenneth G. C.; Holmes, Elaine; Nicholson, Jeremy K.
    Journal of Proteome Research (2020), 19 (11), 4442-4454CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)
    The metabolic effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on human blood plasma were characterized using multiplatform metabolic phenotyping with NMR (NMR) spectroscopy and liq. chromatog.-mass spectrometry (LC-MS). Quant. measurements of lipoprotein subfractions, α-1-acid glycoprotein, glucose, and biogenic amines were made on samples from symptomatic coronavirus disease 19 (COVID-19) patients who had tested pos. for the SARS-CoV-2 virus (n = 17) and from age- and gender-matched controls (n = 25). Data were analyzed using an orthogonal-projections to latent structures (OPLS) method and used to construct an exceptionally strong (AUROC = 1) hybrid NMR-MS model that enabled detailed metabolic discrimination between the groups and their biochem. relationships. Key discriminant metabolites included markers of inflammation including elevated α-1-acid glycoprotein and an increased kynurenine/tryptophan ratio. There was also an abnormal lipoprotein, glucose, and amino acid signature consistent with diabetes and coronary artery disease (low total and HDL Apolipoprotein A1, low HDL triglycerides, high LDL and VLDL triglycerides), plus multiple highly significant amino acid markers of liver dysfunction (including the elevated glutamine/glutamate and Fischer's ratios) that present themselves as part of a distinct SARS-CoV-2 infection pattern. A multivariate training-test set model was validated using independent samples from addnl. SARS-CoV-2 pos. patients and controls. The predictive model showed a sensitivity of 100% for SARS-CoV-2 positivity. The breadth of the disturbed pathways indicates a systemic signature of SARS-CoV-2 positivity that includes elements of liver dysfunction, dyslipidemia, diabetes, and coronary heart disease risk that are consistent with recent reports that COVID-19 is a systemic disease affecting multiple organs and systems. Metabolights study ref.: MTBLS2014.
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    Cutler, D. M. The Costs of Long COVID. JAMA Health Forum. 2022, 3, e221809,  DOI: 10.1001/jamahealthforum.2022.1809
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    Masuda, R.; Lodge, S.; Whiley, L.; Gray, N.; Lawler, N.; Nitschke, P.; Bong, S.-H.; Kimhofer, T.; Loo, R. L.; Boughton, B. Exploration of Human Serum Lipoprotein Supramolecular Phospholipids Using Statistical Heterospectroscopy in n-Dimensions (SHYn): Identification of Potential Cardiovascular Risk Biomarkers Related to SARS-CoV-2 Infection. Anal. Chem. 2022, 94, 4426– 4436
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    Exploration of Human Serum Lipoprotein Supramolecular Phospholipids Using Statistical Heterospectroscopy in n-Dimensions (SHY-n): Identification of Potential Cardiovascular Risk Biomarkers Related to SARS-CoV-2 Infection
    Masuda, Reika; Lodge, Samantha; Whiley, Luke; Gray, Nicola; Lawler, Nathan; Nitschke, Philipp; Bong, Sze-How; Kimhofer, Torben; Loo, Ruey Leng; Boughton, Berin; Zeng, Annie X.; Hall, Drew; Schaefer, Hartmut; Spraul, Manfred; Dwivedi, Girish; Yeap, Bu B.; Diercks, Tammo; Bernardo-Seisdedos, Ganeko; Mato, Jose M.; Lindon, John C.; Holmes, Elaine; Millet, Oscar; Wist, Julien; Nicholson, Jeremy K.
    Analytical Chemistry (Washington, DC, United States) (2022), 94 (10), 4426-4436CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    SARS-CoV-2 infection causes a significant redn. in lipoprotein-bound serum phospholipids give rise to supramol. phospholipid composite (SPC) signals obsd. in diffusion and relaxation edited 1H NMR spectra. 17708906. To characterize the chem. structural components and compartmental location of SPC and to understand further its possible diagnostic properties, we applied a Statistical HeterospectroscopY in n-dimensions (SHY-n) approach. This involved statistically linking a series of orthogonal measurements made on the same samples, using independent anal. techniques and instruments, to identify the major individual phospholipid components giving rise to the SPC signals. Thus, an integrated model for SARS-CoV-2 pos. and control adults is presented that relates three identified diagnostic subregions of the SPC signal envelope (SPC1, SPC2, and SPC3) generated using diffusion and relaxation edited (DIRE) NMR spectroscopy to lipoprotein and lipid measurements obtained by in vitro diagnostic NMR spectroscopy and ultrahigh-performance liq. chromatog.-tandem mass spectrometry (UHPLC-MS/MS). The SPC signals were then correlated sequentially with (a) total phospholipids in lipoprotein subfractions; (b) apolipoproteins B100, A1, and A2 in different lipoproteins and subcompartments; and (c) MS-measured total serum phosphatidylcholines present in the NMR detection range (i.e., PCs: 16.0,18.2; 18.0,18.1; 18.2,18.2; 16.0,18.1; 16.0,20.4; 18.0,18.2; 18.1,18.2), lysophosphatidylcholines (LPCs: 16.0 and 18.2), and sphingomyelin (SM 22.1). The SPC3/SPC2 ratio correlated strongly (r = 0.86) with the apolipoprotein B100/A1 ratio, a well-established marker of cardiovascular disease risk that is markedly elevated during acute SARS-CoV-2 infection. These data indicate the considerable potential of using a serum SPC measurement as a metric of cardiovascular risk based on a single NMR expt. This is of specific interest in relation to understanding the potential for increased cardiovascular risk in COVID-19 patients and risk persistence in post-acute COVID-19 syndrome (PACS).
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    Altered high-density lipoprotein composition is associated with risk for complications in type 2 diabetes mellitus in South Asian descendants: A cross-sectional, case-control study on lipoprotein subclass profiling
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    Compn. of high-d. lipoproteins (HDL) is emerging as an important determinant in the development of microvascular complications in type 2 diabetes mellitus (T2DM). Dutch South Asian (DSA) individuals with T2DM display an increased risk of microvascular complications compared with Dutch white Caucasian (DwC) individuals with T2DM. In this study, we aimed to investigate whether changes in HDL compn. assoc. with increased microvascular risk in this ethnic group and lead to new lipoprotein biomarkers. Using 1H NMR spectroscopy and Bruker IVDr Lipoprotein Subclass Anal. (B.I.LISA) software, plasma lipoprotein changes were detd. in 51 healthy individuals (30 DwC, 21 DSA) and 92 individuals with T2DM (45 DwC, 47 DSA) in a cross-sectional, case-control study. Differential HDL subfractions were investigated using multinomial logistic regression analyses, adjusting for possible confounders including BMI and diabetes duration. We identified HDL compositional differences between healthy and diabetic individuals in both ethnic groups. Specifically, levels of apolipoprotein A2 and HDL-4 subfractions were lower in DSA compared with DwC with T2DM. Apolipoprotein A2 and HDL-4 subfractions also neg. correlated with waist circumference, waist-to-hip ratio, Hb A1c, glucose levels and disease duration in DSA with T2DM, and assocd. with increased incidence of microvascular complications. While HDL compn. differed between controls and T2DM in both ethnic groups, the lower levels of lipid content in the smallest HDL subclass (HDL-4) in DSA with T2DM appeared to be more clin. relevant, with higher odds of having diabetes-related pan-microvascular complications such as retinopathy and neuropathy. These typical differences in HDL could be used as ethnicity-specific T2DM biomarkers.
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    Small high-density lipoprotein and omega-3 fatty acid intake differentiates Japanese and Japanese-Americans: the INTERLIPID study
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    To identify the most differentiated serum lipids, esp. concerning particle size and fractions, between Japanese living in Japan and Japanese-Americans in Hawaii, in the absence of possible genetic confounders, and cross-sectionally examine the assocd. modifiable lifestyle factors. Overall, 1,241 (aged 40-59 years) Japanese living in Japan and Japanese-Americans in Hawaii were included. We quantified 130 serum lipid profiles (VLDL 1-5, IDL, LDL 1-6, high-d. lipoprotein [HDL] 1-4, and their subfractions) using Bruker's 1H-NMR spectrometer for the primary outcome. Modifiable lifestyle factors included body mass index (BMI), phys. activity, alc. and smoking habits, and 70 nutrient parameters. We evaluated the different lipids between the groups using partial least squares-discriminant anal. and assocn. between extd. lipids and lifestyle factors using multivariable linear regression anal. Concns. of HDL4, HDL with the smallest particle size, were lower in Japanese than in Japanese-Americans of both sexes. Higher fish-derived omega-3 fatty acid intake and lower alc. intake were assocd. with lower HDL4 concns. A 1% higher kcal intake of total omega-3 fatty acids was assocd. with a 9.8-mg/dL lower HDL4. Fish-derived docosapentaenoic acid, eicosapentaenoic acid, and docosahexaenoic acid intake were inversely assocd. with HDL4 concn. There was no relationship between country, sex, age, or BMI. Japanese and Japanese-Americans can be differentiated based on HDL4 concn. High fish intake among the Japanese may contribute to their lower HDL4 concn. Thus, HDL particle size may be an important clin. marker for coronary artery diseases or a fish consumption biomarker.
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    Stănciulescu, L.-A.; Scafa, A.; Duduianu, C.; Stan, R.; Nicolescu, A.; Deleanu, C.; Dorobantu, M. Lipoprofiling Assessed by NMR Spectroscopy in Patients with Acute Coronary Syndromes: Is There a Need for Fasting Prior to Sampling. Diagnostics 2022, 12, 1675  DOI: 10.3390/diagnostics12071675
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    Lipoprofiling Assessed by NMR Spectroscopy in Patients with Acute Coronary Syndromes: Is There a Need for Fasting Prior to Sampling?
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    Diagnostics (2022), 12 (7), 1675CODEN: DIAGC9; ISSN:2075-4418. (MDPI AG)
    Most patients presenting in an emergency unit with acute coronary syndromes (ACS) (which include non-ST-elevation myocardial infarction (NSTEMI), ST-elevation MI (STEMI), and unstable angina) usually meet at least two cardiovascular risk factors, such as dyslipidemia, arterial hypertension, diabetes mellitus type 2, obesity, history of or current smoking, etc. Most ACS patients suffer from a type of dyslipidemia, and in addn. to this there are ACS patients rushed into the emergency units for which the feeding status is unknown. Thus, we set out to evaluate the effect of fasting on 16 blood metabolite concns. and 114 lipoprotein parameters on one control group and a group of statin-treated ACS patients hospitalized in a cardiovascular emergency unit, using NMR (NMR) spectroscopy. The results indicated trends (in terms of no. of cases, but not necessarily in terms of the magnitude of the effect) for as many as four metabolites and 48 lipoproteins. The effect was defined as a trend for results showing over 70% of the cases from either one or both groups that experienced parameter changes in the same direction (i.e., either increased or decreased). In terms of magnitude, the effect is rather low, leading to the overall conclusion that in cardiovascular (CV) emergency units, the blood samples analyzed in any feeding status would provide close results and very valuable information regarding prognosis and for fast decisions on patient's proper management.
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    A review. This paper discusses the diabetic dyslipidemia on human serum/plasma lipoprotein anal. by NMR. Introduction to lipoproteins and their role in metab. and the clin. importance of lipoprotein characterization for assessing risk factors important for cardiovascular diseases (CVD). Diffusion-edited NMR pulses will be reviewed in detail because they enhance the NMR signal from lipoproteins and eliminate the signal from small metabolites. Three main approaches: (a) curve fitting methods, which are based on a math. deconvolution of the peak to ext. new features from the lipid peak(s) that will then be used as inputs for multivariate anal.; (b) correlation statistical methods, where the points of the original lipid peak envelop are considered to be input features for further processing algorithms since these methods do not deconvolute the peak; and (c) diffusion NMR methods.
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    Comparison of capillary and venous blood sampling for routine coagulation assays
    Fliervoet, Lies A. L.; Tiel Groenestege, Wouter M.; Huisman, Albert
    Clinical Biochemistry (2022), 104 (), 30-35CODEN: CLBIAS; ISSN:0009-9120. (Elsevier B.V.)
    Capillary blood samples are generally assumed as unsuitable for coagulation testing since it is recognized that contamination with tissue factor and diln. with tissue fluid affects the coagulation assay. However, limited data is available about coagulations assays in which capillary blood sampling is compared to the std. venous blood withdrawal method. The aim of this study was to perform a method comparison between capillary and venous blood sampling for routine coagulation assays. Both venous and capillary (finger stick) blood samples were collected from 188 healthy volunteers and patients. In citrate plasma, International Normalized Ratio (INR), prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen, and D-dimer were measured according to routine protocols using the ACL-TOP 750 LAS (Werfen) coagulation analyzer. Regression anal. was performed and the mean relative difference between capillary and venous sampling was reflected to the total allowable error (TEa). Strong correlations and acceptable variations, using the TEa as decision limit, were found for INR, PT, TT, fibrinogen, and D-dimer between capillary and venous sampling. However, capillary sampling resulted in significant shorter APTT values when using the std. APTT-SP Liq. reagent with a mean bias of -10.4% [95% CI -12.4 to -8.4]. Based on these results, capillary blood sampling proved to be an alternative blood withdrawal method for routine coagulation assays, with the exception of APTT, if a venipuncture is unavailable or undesired.
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  1. Luke Whiley, Nathan G. Lawler, Annie Xu Zeng, Alex Lee, Sung-Tong Chin, Maider Bizkarguenaga, Chiara Bruzzone, Nieves Embade, Julien Wist, Elaine Holmes, Oscar Millet, Jeremy K. Nicholson, Nicola Gray. Cross-Validation of Metabolic Phenotypes in SARS-CoV-2 Infected Subpopulations Using Targeted Liquid Chromatography–Mass Spectrometry (LC-MS). Journal of Proteome Research 2024, 23 (4) , 1313-1327. https://doi.org/10.1021/acs.jproteome.3c00797
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  • Abstract

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    Figure 1

    Figure 1. Sample collection workflow for 1H NMR. (A) Evaluating the comparability between venous and capillary blood sampling sites; (B) 3-day assessment of venous technical replicate standard error for 3 mm outer diameter SampleJet NMR tubes; (C) preliminary comparison of low-field spectra: (V) = venous, (C) capillary, (s) = serum, and (p) = plasma. Image created with BioRender.com.

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    Figure 2

    Figure 2. Median proton NMR spectra from all study participants for 1D and JEDI-PGPE experiments. Plasma and serum represent spectra of the capillary and venous samples collected from a clinical visit (N = 20). Capillary spectra (green and red traces) are overlaid with venous (black traces) derived in the 1D and PGPE experiments. Expansions of the SPC and Glyc regions from the latter demonstrate an overlap between capillary and venous samples in both plasma and serum. In serum samples, a small difference in the low-frequency portion of SPC1, corresponding to HDL-4, is witnessed. 3-Day replicates represent spectra of venous plasma collected from two clinical visits (N = 12).

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    Figure 3

    Figure 3. Relationship and variation of plasma and serum analyte concentrations between the different collection sites. Adjusted R2 for plasma (green) and serum (red) with corresponding standard error percentage (SE%, black) for capillary vs venous lipoproteins (LIPO, VLDL, LDL, HDL), supramolecular phospholipid composites (SPCs), and glycoprotein acetyls (Glycs) parameters. For plasma, collection site SE% is overlaid with SE% of 3-day replicates of venous plasma acquired in 3 mm outer diameter NMR SampleJet tubes (blue). Hollow circles indicate parameters where the standard error percentage is lower for the 3-day 3 mm venous plasma analysis than the error between venous and capillary and Adj. R2 < 0.80. For serum, only the latter rule applies. A descriptive list of the abbreviated lipoprotein main fractions, subfractions, SPCs, and Glycs (gray labels) are reported in Table S1.

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    Figure 4. Preliminary direct low-field 80 MHz 1H NMR spectra. 1D and JEDI-PGSE spectra of capillary (green trace) and venous (black trace) plasma samples collected from two participants (PT.1 = left, PT.2 = right). Capillary spectra overlay with venous spectra for SPC and Glyc measurements from the PGSE experiment.

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      Advanced Microsamples: Current Applications and Considerations for Mass Spectrometry-Based Metabolic Phenotyping Pipelines
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      Separations (2022), 9 (7), 175CODEN: SEPAF2; ISSN:2297-8739. (MDPI AG)
      A review. Microsamples are collections usually less than 50μL, although all devices that we have captured as part of this review do not fit within this definition (as some can perform collections of up to 600μL); however, they are considered microsamples that can be self-administered. These microsamples have been introduced in pre-clin., clin., and research settings to overcome obstacles in sampling via traditional venepuncture. However, venepuncture remains the sampling gold std. for the metabolic phenotyping of blood. This presents several challenges in metabolic phenotyping workflows: accessibility for individuals in rural and remote areas (due to the need for trained personnel), the unamenable nature to frequent sampling protocols in longitudinal research (for its invasive nature), and sample collection difficulty in the young and elderly. Furthermore, venous sample stability may be compromised when the temperate conditions necessary for cold-chain transport are beyond control. Alternatively, research utilizing microsamples extends phenotyping possibilities to inborn errors of metab., therapeutic drug monitoring, nutrition, as well as sport and anti-doping. Although the application of microsamples in metabolic phenotyping exists, it is still in its infancy, with whole blood being overwhelmingly the primary biofluid collected through the collection method of dried blood spots. Research into the metabolic phenotyping of microsamples is limited; however, with advances in com. available microsampling devices, common barriers such as volumetric inaccuracies and the 'haematocrit effect' in dried blood spot microsampling can be overcome. In this review, we provide an overview of the common uses and workflows for microsampling in metabolic phenotyping research. We discuss the advancements in technologies, highlighting key considerations and remaining knowledge gaps for the employment of microsamples in metabolic phenotyping research. This review supports the translation of research from the 'bench to the community'.
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      Ten years ago, the proposition that healthcare is evolving from reactive disease care to care that is predictive, preventive, personalized and participatory was regarded as highly speculative. Today, the core elements of that vision are widely accepted and have been articulated in a series of recent reports by the US Institute of Medicine. Systems approaches to biol. and medicine are now beginning to provide patients, consumers and physicians with personalized information about each individual's unique health experience of both health and disease at the mol., cellular and organ levels. This information will make disease care radically more cost effective by personalizing care to each person's unique biol. and by treating the causes rather than the symptoms of disease. It will also provide the basis for concrete action by consumers to improve their health as they observe the impact of lifestyle decisions. Working together in digitally powered familial and affinity networks, consumers will be able to reduce the incidence of the complex chronic diseases that currently account for 75% of disease-care costs in the USA.
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      750 MHz 1H and 1H-13C NMR Spectroscopy of Human Blood Plasma
      Nicholson, Jeremy K.; Foxall, Peta J. D.; Spraul, Manfred; Farrant, R. Duncan; Lindon, John C.
      Analytical Chemistry (1995), 67 (5), 793-811CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      High-resoln. 750 MHz 1H NMR spectra of control human blood plasma have been measured and assigned by the concerted use of a range of spin-echo, two-dimensional J-resolved, and homonuclear and heteronuclear (1H-13C) correlation methods. The increased spectral dispersion and sensitivity at 750 MHz enable the assignment of numerous 1H and 13C resonances from many mol. species that cannot be detected at lower frequencies. This work presents the most comprehensive assignment of the 1H NMR spectra of blood plasma yet achieved and includes the assignment of signals from 43 low Mr metabolites, including many with complex or strongly coupled spin systems. New assignments are also provided from the 1H and 13C NMR signals from several important macromol. species in whole blood plasma, i.e., very-low-d., low-d., and high-d. lipoproteins, albumin, and α1-acid glycoprotein. The temp. dependence of the one-dimensional and spin-echo 750 MHz 1H NMR spectra of plasma was investigated over the range 292-310 K. The 1H NMR signals from the fatty acyl side chains of the lipoproteins increased substantially with temp. (hence also mol. mobility), with a disproportionate increase from lipids in low-d. lipoprotein. Two-dimensional 1H-13C heteronuclear multiple quantum coherence spectroscopy at 292 and 310 K allowed both the direct detection of cholesterol and choline species bound in high-d. lipoprotein and the assignment of their signals and confirmed the assignment of most of the lipoprotein resonances.
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      Nicholson, J. K.; O’Flynn, M. P.; Sadler, P. J.; Macleod, A. F.; Juul, S. M.; Sönksen, P. H. Proton-nuclear-magnetic-resonance studies of serum, plasma and urine from fasting normal and diabetic subjects. Biochem. J. 1984, 217, 365– 375,  DOI: 10.1042/bj2170365
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      Proton-nuclear-magnetic-resonance studies of serum, plasma and urine from fasting normal and diabetic subjects
      Nicholson J K; O'Flynn M P; Sadler P J; Macleod A F; Juul S M; Sonksen P H
      The Biochemical journal (1984), 217 (2), 365-75 ISSN:0264-6021.
      Resonances for the ketone bodies 3-D-hydroxybutyrate, acetone and acetoacetate are readily detected in serum, plasma and urine samples from fasting and diabetic subjects by 1H n.m.r. spectroscopy at 400 MHz. Besides the simultaneous observation of metabolites, the major advantage of n.m.r. is that little or no pretreatment of samples is required. N.m.r. determinations of 3-D-hydroxybutyrate, acetoacetate, lactate, valine and alanine were compared with determinations made with conventional assays at six 2-hourly intervals after insulin withdrawal from a diabetic subject. The n.m.r. results closely paralleled those of other assays although, by n.m.r., acetoacetate levels continued to rise rather than reaching a plateau 4h after insulin withdrawal. The 3-D-hydroxybutyrate/acetoacetate ratio in urine during withdrawal gradually increased to the value observed in plasma (3.0 +/- 0.2) as determined by n.m.r. The acetoacetate/acetone ratio in urine (17 +/- 6) was much higher than in plasma (2.5 +/- 0.7). Depletion of a mobile pool of fatty acids in plasma during fasting, as seen by n.m.r., paralleled that seen during insulin withdrawal. These fatty acids were thought to be largely in chylomicrons, acylglycerols and lipoproteins, and were grossly elevated in plasma samples from a non-insulin-dependent diabetic and in cases of known hyperlipidaemia.
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      Proton NMR studies of human blood plasma. Assignment of resonances for lipoproteins
      Bell, Jimmy D.; Sadler, Peter J.; Macleod, Andrew F.; Turner, Peter R.; La Ville, Agnes
      FEBS Letters (1987), 219 (1), 239-43CODEN: FEBLAL; ISSN:0014-5793.
      Single-pulse and Hahn spin-echo 500 MHz 1H-NMR spectra of human blood plasma and isolated chylomicrons and very-low-d., low-d., and high-d. lipoproteins are reported. The comparison has enable specific assignments to be made for the resonances of individual lipoproteins in the CH2 and CH3 (fatty acid), and NMe3+ (phospholipid choline head group) regions of the spectra of plasma (0.8-1.3 and ∼3.25 ppm, resp.). Fasting and freeze-thawing of plasma samples led to marked changes in the intensities and linewidths of lipid resonances. Anal. of lipid resonances in the spectra of plasma in terms of individual lipoproteins may shed new light on many conditions of clin. and biochem. interest.
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    8. 8
      Nicholson, J. K.; Buckingham, M. J.; Sadler, P. J. High resolution 1H n.m.r. studies of vertebrate blood and plasma. Biochem. J. 1983, 211, 605– 615,  DOI: 10.1042/bj2110605
      8
      High resolution proton NMR studies of vertebrate blood and plasma
      Nicholson, Jeremy K.; Buckingham, Malcolm J.; Sadler, Peter J.
      Biochemical Journal (1983), 211 (3), 605-15CODEN: BIJOAK; ISSN:0264-6021.
      Spin-echo Fourier-transform proton NMR spectra of whole blood contain resonances from both erythrocytes and plasma. A large no. of well-resolved signals from mobile protons of low-mol.-wt. metabolites in plasma and serum were identified. Spectra from the plasmas of 8 animal species and com. quality control sera were comparable. CaEDTA2- and MgEDTA2- resonances can be used for the simultaneous detn. of EDTA-chelatable Ca and Mg concns. in intact plasma and other biol. fluids. Cholesterol is too immobile to contribute to the spectra of intact plasma, but is readily estd. by NMR in both its free and esterified forms after extn. into MeOH.
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    9. 9
      Nicholson, J. K.; Wilson, I. D. High resolution proton magnetic resonance spectroscopy of biological fluids. Prog. Nucl. Magn. Reson. Spectrosc. 1989, 21, 449– 501,  DOI: 10.1016/0079-6565(89)80008-1
      9
      High resolution proton magnetic resonance spectroscopy of biological fluids
      Nicholson, Jeremy K.; Wilson, Ian D.
      Progress in Nuclear Magnetic Resonance Spectroscopy (1989), 21 (4-5), 449-501CODEN: PNMRAT; ISSN:0079-6565.
      A review, with 129 refs., the title subject with emphasis on practical considerations of 1H-NMR of biofluids; the biochem., physicochem., and NMR properties of humans and animal body fluids; clin. applications; application in drug metab.; toxicol. applications; and pattern recognition approaches to the interpretation of NMR generated toxicol. data.
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    10. 10
      Lamarche, B.; Tchernof, A.; Moorjani, S.; Cantin, B.; Dagenais, G. R.; Lupien, P. J.; Despre′s, J.-P. Small, Dense Low-Density Lipoprotein Particles as a Predictor of the Risk of Ischemic Heart Disease in Men. Circulation 1997, 95, 69– 75,  DOI: 10.1161/01.CIR.95.1.69
      10
      Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study
      Lamarche B; Tchernof A; Moorjani S; Cantin B; Dagenais G R; Lupien P J; Despres J P
      Circulation (1997), 95 (1), 69-75 ISSN:0009-7322.
      BACKGROUND: Case-control studies have reported that patients with ischemic heart disease (IHD) have a higher proportion of small, dense LDL particles than do healthy control subjects. The extent to which the risk attributed to small LDL particles may be independent of concomitant variations in plasma lipoprotein-lipid concentrations remains to be clearly determined, however, particularly through prospective studies. METHODS AND RESULTS: Baseline characteristics were obtained in 2103 men initially free of IHD, among whom 114 developed IHD during a 5-year follow-up period. These 114 case patients were matched with healthy control subjects for age, body mass index, smoking habits, and alcohol intake. LDL peak particle diameter (PPD) was measured a posteriori in 103 case-control pairs by nondenaturing gradient gel electrophoresis of whole plasma. Conditional logistic regression analysis of the case-control status revealed that men in the first tertile of the control LDL-PPD distribution (LDL-PPD < or = 25.64 nm) had a 3.6-fold increase in the risk of IHD (95% CI, 1.5 to 8.8) compared with those in the third tertile (LDL-PPD > 26.05 nm). Statistical adjustment for concomitant variations in LDL cholesterol, triglycerides, HDL cholesterol, and apolipoprotein B concentrations had virtually no impact on the relationship between small LDL particles and the risk of IHD. CONCLUSIONS: These results represent the first prospective evidence suggesting that the presence of small, dense LDL particles may be associated with an increased risk of subsequently developing IHD in men. Results also suggest that the risk attributed to small LDL particles may be partly independent of the concomitant variation in plasma lipoprotein-lipid concentrations.
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    11. 11
      Jiménez, B.; Holmes, E.; Heude, C.; Tolson, R. F.; Harvey, N.; Lodge, S. L.; Chetwynd, A. J.; Cannet, C.; Fang, F.; Pearce, J. T. M. Quantitative Lipoprotein Subclass and Low Molecular Weight Metabolite Analysis in Human Serum and Plasma by 1H NMR Spectroscopy in a Multilaboratory Trial. Anal. Chem. 2018, 90, 11962– 11971,  DOI: 10.1021/acs.analchem.8b02412
      11
      Quantitative Lipoprotein Subclass and Low Molecular Weight Metabolite Analysis in Human Serum and Plasma by 1H NMR Spectroscopy in a Multilaboratory Trial
      Jimenez, Beatriz; Holmes, Elaine; Heude, Clement; Tolson, Rose F.; Harvey, Nikita; Lodge, Samantha L.; Chetwynd, Andrew J.; Cannet, Claire; Fang, Fang; Pearce, Jake T. M.; Lewis, Matthew R.; Viant, Mark R.; Lindon, John C.; Spraul, Manfred; Schafer, Hartmut; Nicholson, Jeremy K.
      Analytical Chemistry (Washington, DC, United States) (2018), 90 (20), 11962-11971CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      We report an extensive 600 MHz NMR trial of quant. lipoprotein and small-mol. measurements in human blood serum and plasma. Five centers with eleven 600 MHz NMR spectrometers were used to analyze 98 samples including 20 quality controls (QCs), 37 com. sourced, paired serum and plasma samples, and two National Institute of Science and Technol. (NIST) ref. material 1951c replicates. Samples were analyzed using rigorous protocols for sample prepn. and exptl. acquisition. A com. lipoprotein subclass anal. was used to quantify 105 lipoprotein subclasses and 24 low mol. wt. metabolites from the NMR spectra. For all spectrometers, the instrument specific variance in measuring internal QCs was lower than the percentage described by the National Cholesterol Education Program (NCEP) criteria for lipid testing [triglycerides <2.7%; cholesterol <2.8%; low-d. lipoprotein (LDL) cholesterol <2.8%; high-d. lipoprotein (HDL) cholesterol <2.3%], showing exceptional reproducibility for direct quantitation of lipoproteins in both matrixes. The av. relative std. deviations (RSDs) for the 105 lipoprotein parameters in the 11 instruments were 4.6% and 3.9% for the two NIST samples, whereas they were 38% and 40% for the 37 com. sourced plasmas and sera, resp., showing negligible anal. compared to biol. variation. The coeff. of variance (CV) obtained for the quantification of the small mols. across the 11 spectrometers was below 15% for 20 out of the 24 metabolites analyzed. This study provides further evidence of the suitability of NMR for high-throughput lipoprotein subcomponent anal. and small-mol. quantitation with the exceptional required reproducibility for clin. and other regulatory settings.
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    12. 12
      Lodge, S.; Nitschke, P.; Loo, R. L.; Kimhofer, T.; Bong, S.-H.; Richards, T.; Begum, S.; Spraul, M.; Schaefer, H.; Lindon, J. C. Low Volume in Vitro Diagnostic Proton NMR Spectroscopy of Human Blood Plasma for Lipoprotein and Metabolite Analysis: Application to SARS-CoV-2 Biomarkers. J. Proteome Res. 2021, 20, 1415– 1423,  DOI: 10.1021/acs.jproteome.0c00815
      12
      Low Volume in Vitro Diagnostic Proton NMR Spectroscopy of Human Blood Plasma for Lipoprotein and Metabolite Analysis: Application to SARS-CoV-2 Biomarkers
      Lodge, Samantha; Nitschke, Philipp; Loo, Ruey Leng; Kimhofer, Torben; Bong, Sze-How; Richards, Toby; Begum, Sofina; Spraul, Manfred; Schaefer, Hartmut; Lindon, John C.; Holmes, Elaine; Nicholson, Jeremy K.
      Journal of Proteome Research (2021), 20 (2), 1415-1423CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)
      The utility of low sample vol. in vitro diagnostic (IVDr) proton NMR (1H NMR) spectroscopic expts. on blood plasma for information recovery from limited availability or high value samples was exemplified using plasma from patients with SARS-CoV-2 infection and normal controls. 1H NMR spectra were obtained using solvent-suppressed 1D, spin-echo (CPMG), and 2-dimensional J-resolved (JRES) spectroscopy using both 3 mm outer diam. SampleJet NMR tubes (100μL plasma) and 5 mm SampleJet NMR tubes (300μL plasma) under in vitro diagnostic conditions. We noted near identical diagnostic models in both std. and low vol. IVDr lipoprotein anal. (measuring 112 lipoprotein parameters) with a comparison of the two tubes yielding R2 values ranging between 0.82 and 0.99 for the 40 paired lipoprotein parameters samples. Lipoprotein measurements for the 3 mm tubes were achieved without time penalty over the 5 mm tubes as defined by biomarker recovery for SARS-CoV-2. Overall, biomarker pattern recovery for the lipoproteins was extremely similar, but there were some small pos. offsets in the linear equations for several variables due to small shimming artifacts, but there was minimal degrdn. of the biol. information. For the std. untargeted 1D, CPMG, and JRES NMR expts. on the same samples, the reduced signal-to-noise was more constraining and required greater scanning times to achieve similar differential diagnostic performance (15 min per sample per expt. for 3 mm 1D and CPMG, compared to 4 min for the 5 mm tubes). We conclude that the 3 mm IVDr method is fit-for-purpose for quant. lipoprotein measurements, allowing the prepn. of smaller vols. for high value or limited vol. samples that is common in clin. studies. If there are no anal. time constraints, the lower vol. expts. are equally informative for untargeted profiling.
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    13. 13
      Dona, A. C.; Jiménez, B.; Schäfer, H.; Humpfer, E.; Spraul, M.; Lewis, M. R.; Pearce, J. T. M.; Holmes, E.; Lindon, J. C.; Nicholson, J. K. Precision High-Throughput Proton NMR Spectroscopy of Human Urine, Serum, and Plasma for Large-Scale Metabolic Phenotyping. Anal. Chem. 2014, 86, 9887– 9894,  DOI: 10.1021/ac5025039
      13
      Precision High-Throughput Proton NMR Spectroscopy of Human Urine, Serum, and Plasma for Large-Scale Metabolic Phenotyping
      Dona, Anthony C.; Jimenez, Beatriz; Schafer, Hartmut; Humpfer, Eberhard; Spraul, Manfred; Lewis, Matthew R.; Pearce, Jake T. M.; Holmes, Elaine; Lindon, John C.; Nicholson, Jeremy K.
      Analytical Chemistry (Washington, DC, United States) (2014), 86 (19), 9887-9894CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      Proton NMR-based metabolic phenotyping of urine and blood plasma/serum samples provides important prognostic and diagnostic information and permits monitoring of disease progression in an objective manner. Much effort has been made in recent years to develop NMR instrumentation and technol. to allow the acquisition of data in an effective, reproducible, and high-throughput approach that allows the study of general population samples from epidemiol. collections for biomarkers of disease risk. The challenge remains to develop highly reproducible methods and standardized protocols that minimize tech. or exptl. bias, allowing realistic interlab. comparisons of subtle biomarker information. Here the authors present a detailed set of updated protocols that carefully consider major exptl. conditions, including sample prepn., spectrometer parameters, NMR pulse sequences, throughput, reproducibility, quality control, and resoln. These results provide an exptl. platform that facilitates NMR spectroscopy usage across different large cohorts of biofluid samples, enabling integration of global metabolic profiling that is a prerequisite for personalized healthcare.
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    14. 14
      Otvos, J. D.; Shalaurova, I.; Wolak-Dinsmore, J.; Connelly, M. A.; Mackey, R. H.; Stein, J. H.; Tracy, R. P. GlycA: A Composite Nuclear Magnetic Resonance Biomarker of Systemic Inflammation. Clin. Chem. 2015, 61, 714– 723,  DOI: 10.1373/clinchem.2014.232918
      14
      GlycA: a composite nuclear magnetic resonance biomarker of systemic inflammation
      Otvos, James D.; Shalaurova, Irina; Wolak-Dinsmore, Justyna; Connelly, Margery A.; Mackey, Rachel H.; Stein, James H.; Tracy, Russell P.
      Clinical Chemistry (Washington, DC, United States) (2015), 61 (5), 714-723CODEN: CLCHAU; ISSN:0009-9147. (American Association for Clinical Chemistry)
      NMR (NMR) spectra of serum obtained under quant. conditions for lipoprotein particle analyses contain addnl. signals that could potentially serve as useful clin. biomarkers. One of these signals that we named GlycA originates from a subset of glycan N-acetylglucosamine residues on enzymically glycosylated acute-phase proteins. We hypothesized that the amplitude of the GlycA signal might provide a unique and convenient measure of systemic inflammation. We developed a spectral deconvolution algorithm to quantify GlycA signal amplitudes from automated NMR LipoProfile test spectra and assessed analytic precision and biol. variability. Spectra of acute-phase glycoproteins and serum fractions were analyzed to probe the origins of the GlycA signal. GlycA concns. obtained from archived NMR LipoProfile spectra of baseline plasma from 5537 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) were used to assess assocns. with demog. and lab. parameters including measures of inflammation. Major acute-phase protein contributors to the serum GlycA signal are α1-acid glycoprotein, haptoglobin, α1-antitrypsin, α1-antichymotrypsin, and transferrin. GlycA concns. were correlated with high-sensitivity C-reactive protein (hsCRP) (r = 0.56), fibrinogen (r = 0.46), and interleukin-6 (IL-6) (r = 0.35) (all P < 0.0001). Analytic imprecision was low (intra- and interassay CVs 1.9% and 2.6%, resp.) and intraindividual variability, assessed weekly for 5 wk in 23 healthy volunteers, was 4.3%, lower than for hsCRP (29.2%), cholesterol (5.7%), and triglycerides (18.0%). GlycA is a unique inflammatory biomarker with analytic and clin. attributes that may complement or provide advantages over existing clin. markers of systemic inflammation.
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    15. 15
      Otvos, J. D.; Jeyarajah, E. J.; Bennett, D. W. Quantification of plasma lipoproteins by proton nuclear magnetic resonance spectroscopy. Clin. Chem. 1991, 37, 377– 386,  DOI: 10.1093/clinchem/37.3.377
      15
      Quantification of plasma lipoproteins by proton nuclear magnetic resonance spectroscopy
      Otvos, J. D.; Jeyarajah, E. J.; Bennett, D. W.
      Clinical Chemistry (Washington, DC, United States) (1991), 37 (3), 377-86CODEN: CLCHAU; ISSN:0009-9147.
      A new anal. procedure for quantifying plasma lipoproteins by proton NMR spectroscopy has been developed that potentially offers significant advantages over existing clin. methods used for assessing risk of coronary heart disease. Anal. of a single spectrum of a nonfasting plasma sample, acquired simply and rapidly at moderate magnetic field strength (250 MHz), yields a complete profile of lipoprotein concns.: chylomicrons and very-low-, low-, and high-d. lipoproteins. The method is based on curve-fitting (spectral deconvolution) of the plasma Me lipid resonance envelope, the amplitude and shape of which depend directly on the amplitudes of the superimposed Me resonances of the lipoprotein components. A linear least-squares curve-fitting algorithm was developed to efficiently ext. the signal amplitudes (concns.) of the lipoproteins from the plasma spectrum. These signal amplitudes correlate well with lipoprotein concns. detd. by triglyceride and cholesterol measurements.
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    16. 16
      Ala-Korpela, M.; Korhonen, A.; Keisala, J.; Hörkkö, S.; Korpi, P.; Ingman, L. P.; Jokisaari, J.; Savolainen, M. J.; Kesäniemi, Y. A. 1H NMR-based absolute quantitation of human lipoproteins and their lipid contents directly from plasma. J. Lipid Res. 1994, 35, 2292– 2304,  DOI: 10.1016/S0022-2275(20)39935-1
      16
      1H NMR-based absolute quantitation of human lipoproteins and their lipid contents directly from plasma
      Ala-Korpela, M.; Korhonen, A.; Keisala, J.; Hoerkkoe, S.; Korpi, P.; Ingman, L. P.; Jokisaari, J.; Savolainen, M. J.; Kesaeniemi, Y. A.
      Journal of Lipid Research (1994), 35 (12), 2292-304CODEN: JLPRAW; ISSN:0022-2275. (Lipid Research, Inc.)
      A new method is presented for abs. quantitation of lipid and protein contents of human lipoproteins directly from plasma. The method enables complete lipoprotein lipid profiles to be obtained in a total time of less than one hour. Abs. concns. of triglycerides, phospholipids, total cholesterol, free cholesterol, esterified cholesterol, total proteins, and total masses can be estd. for the very low d. (VLDL) and low d. (LDL) lipoprotein fractions. For the high d. lipoprotein (HDL) fraction all components except triglycerides can be quantitated. The method is a combination of 1H NMR spectroscopy and a sophisticated lineshape fitting anal. technique. In this paper we present the calibration of the method using 15 plasma samples followed by a double-blind test of 51 plasma samples from 43 individuals. In total, 66 plasma samples were analyzed. Comparison of the 1H NMR-based results with the data of the biochem. assays showed excellent agreement; the correlation coeff. for VLDL triglycerides was 0.98, for LDL cholesterol 0.88, and for HDL cholesterol 0.93. This method can be directly integrated to many kinds of biomedical NMR studies to offer addnl. biochem. important quant. lipoprotein information, the measurement of which is usually to laborious by conventional biochem. methods and too high-priced to be adapted into the study protocols. Moreover, the method also has considerable potential to be developed for a routine clin. assay.
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    17. 17
      Bell, J. D.; Brown, J. C. C.; Nicholson, J. K.; Sadler, P. J. Assignment of resonances for ‘acute-phase’ glycoproteins in high resolution proton NMR spectra of human blood plasma. FEBS Lett. 1987, 215, 311– 315,  DOI: 10.1016/0014-5793(87)80168-0
      17
      Assignment of resonances for 'acute-phase' glycoproteins in high resolution proton NMR spectra of human blood plasma
      Bell, J. D.; Brown, J. C. C.; Nicholson, J. K.; Sadler, P. J.
      FEBS Letters (1987), 215 (2), 311-15CODEN: FEBLAL; ISSN:0014-5793.
      Broad resonances at 2.04 and 2.08 ppm in 500 MHz Hahn spin-echo 1H NMR spectra of human blood plasma are assigned to the N-acetyl groups of mobile carbohydrate side-chains (largely N-acetylglucosamine and N-acetylneuraminic acid) of glycoproteins such as α1-acid glycoprotein. Their intensities in spin-echo spectra correlate with clin. conditions in which an elevation of the level of acute-phase glycoproteins is expected, and so may be of value in the study of certain diseases.
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    18. 18
      Nitschke, P.; Lodge, S.; Hall, D.; Schaefer, H.; Spraul, M.; Embade, N.; Millet, O.; Holmes, E.; Wist, J.; Nicholson, J. K. Direct low field J-edited diffusional proton NMR spectroscopic measurement of COVID-19 inflammatory biomarkers in human serum. Analyst 2022, 147, 4213– 4221,  DOI: 10.1039/D2AN01097F
      18
      Direct low field J-edited diffusional proton NMR spectroscopic measurement of COVID-19 inflammatory biomarkers in human serum
      Nitschke, Philipp; Lodge, Samantha; Hall, Drew; Schaefer, Hartmut; Spraul, Manfred; Embade, Nieves; Millet, Oscar; Holmes, Elaine; Wist, Julien; Nicholson, Jeremy K.
      Analyst (Cambridge, United Kingdom) (2022), 147 (19), 4213-4221CODEN: ANALAO; ISSN:0003-2654. (Royal Society of Chemistry)
      A JEDI NMR pulse expt. incorporating relaxational, diffusional and J-modulation peak editing has been implemented for a low field (80 MHz proton resonance frequency) spectrometer system to measure quant. two recently discovered plasma markers of SARS-CoV-2 infection and general inflammation. JEDI spectra capture a unique signature of two biomarker signals from acetylated glycoproteins (Glyc) and the supramol. phospholipid composite (SPC) signals that are relatively enhanced by the combination of relaxation, diffusion and J-editing properties of the JEDI expt. that strongly attenuate contributions from the other mol. species in plasma. The SPC/Glyc ratio data were essentially identical in the 600 MHz and 80 MHz spectra obtained (R2 = 0.97) and showed significantly different ratios for control (n = 28) vs. SARS-CoV-2 pos. patients (n = 29) (p = 5.2 x 10-8 and 3.7 x 10-8 resp.). Simplification of the sample prepn. allows for data acquisition in a similar time frame to high field machines (∼4 min) and a high-throughput version with 1 min expt. time could be feasible. These data show that these newly discovered inflammatory biomarkers can be measured effectively on low field NMR instruments that do not not require housing in a complex lab. environment, thus lowering the barrier to clin. translation of this diagnostic technol.
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    19. 19
      Lodge, S.; Nitschke, P.; Kimhofer, T.; Coudert, J. D.; Begum, S.; Bong, S.-H.; Richards, T.; Edgar, D.; Raby, E.; Spraul, M. NMR Spectroscopic Windows on the Systemic Effects of SARS-CoV-2 Infection on Plasma Lipoproteins and Metabolites in Relation to Circulating Cytokines. J. Proteome Res. 2021, 20, 1382– 1396,  DOI: 10.1021/acs.jproteome.0c00876
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      NMR Spectroscopic Windows on the Systemic Effects of SARS-CoV-2 Infection on Plasma Lipoproteins and Metabolites in Relation to Circulating Cytokines
      Lodge, Samantha; Nitschke, Philipp; Kimhofer, Torben; Coudert, Jerome D.; Begum, Sofina; Bong, Sze-How; Richards, Toby; Edgar, Dale; Raby, Edward; Spraul, Manfred; Schaefer, Hartmut; Lindon, John C.; Loo, Ruey Leng; Holmes, Elaine; Nicholson, Jeremy K.
      Journal of Proteome Research (2021), 20 (2), 1382-1396CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)
      To investigate the systemic metabolic effects of SARS-CoV-2 infection, we analyzed 1H NMR spectroscopic data on human blood plasma and co-modeled with multiple plasma cytokines and chemokines (measured in parallel). Thus, 600 MHz 1H solvent-suppressed single-pulse, spin-echo, and 2D J-resolved spectra were collected on plasma recorded from SARS-CoV-2 rRT-PCR-pos. patients (n = 15, with multiple sampling timepoints) and age-matched healthy controls (n = 34, confirmed rRT-PCR neg.), together with patients with COVID-19/influenza-like clin. symptoms who tested SARS-CoV-2 neg. (n = 35). We compared the single-pulse NMR spectral data with in vitro diagnostic research (IVDr) information on quant. lipoprotein profiles (112 parameters) extd. from the raw 1D NMR data. All NMR methods gave highly significant discrimination of SARS-CoV-2 pos. patients from controls and SARS-CoV-2 neg. patients with individual NMR methods, giving different diagnostic information windows on disease-induced phenoconversion. Longitudinal trajectory anal. in selected patients indicated that metabolic recovery was incomplete in individuals without detectable virus in the recovery phase. We obsd. four plasma cytokine clusters that expressed complex differential statistical relationships with multiple lipoproteins and metabolites. These included the following: cluster 1, comprising MIP-1β, SDF-1α, IL-22, and IL-1α, which correlated with multiple increased LDL and VLDL subfractions; cluster 2, including IL-10 and IL-17A, which was only weakly linked to the lipoprotein profile; cluster 3, which included IL-8 and MCP-1 and were inversely correlated with multiple lipoproteins. IL-18, IL-6, and IFN-γ together with IP-10 and RANTES exhibited strong pos. correlations with LDL1-4 subfractions and neg. correlations with multiple HDL subfractions. Collectively, these data show a distinct pattern indicative of a multilevel cellular immune response to SARS CoV-2 infection interacting with the plasma lipoproteome giving a strong and characteristic immunometabolic phenotype of the disease. We obsd. that some patients in the respiratory recovery phase and testing virus-free were still metabolically highly abnormal, which indicates a new role for these technologies in assessing full systemic recovery.
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    20. 20
      Walldius, G.; Jungner, I.; Holme, I.; Aastveit, A. H.; Kolar, W.; Steiner, E. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet 2001, 358, 2026– 2033,  DOI: 10.1016/S0140-6736(01)07098-2
      20
      High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study
      Walldius, Goran; Jungner, Ingmar; Holme, Ingar; Aastveit, Are H.; Kolar, Werner; Steiner, Eugen
      Lancet (2001), 358 (9298), 2026-2033CODEN: LANCAO; ISSN:0140-6736. (Lancet Ltd.)
      Background: Apolipoprotein B (apoB) and apolipoprotein A-I (apoA-I) are thought to be better predictors of acute myocardial infarction than total cholesterol and LDL-cholesterol. We investigated whether apoB and apoA-I are predictors of risk of fatal myocardial infarction. We also aimed to establish whether apoB and apoA-I add further information about risk of fatal myocardial infarction to that obtained with total cholesterol, triglycerides, and LDL-cholesterol. Methods: We recruited 175553 individuals mainly from screening programs. We measured concns. of apoB, apoA-I, total cholesterol, and triglycerides, and calcd. apoB/apoA-I ratio and concns. of LDL-cholesterol and HDL-cholesterol. The relation between death from acute myocardial infarction and initial values for apoB, apoA-I, and the other lipids was examd. Findings: Mean follow-up was 66·8 mo (SD 41·3) for 98722 men and 64·4 mo (41·4) for 76831 women. 864 Men and 359 women had fatal myocardial infarction. In univariate analyses adjusted for age and in multivariate analyses adjusted for age, total cholesterol, and triglycerides, the values for apoB and apoB/apoA-I ratio were strongly and pos. related to increased risk of fatal myocardial infarction in men and in women. ApoA-I was noted to be protective. In multivariate anal., apoB was a stronger predictor of risk than LDL-cholesterol in both sexes. Interpretation: Although LDL-cholesterol and HDL-cholesterol are known risk factors, we suggest that apoB, apoB/apoA-I, and apoA-I should also be regarded as highly predictive in evaluation of cardiac risk. Although increased throughout the range of values of LDL-cholesterol, apoB and apoA-I might be of greatest value in diagnosis and treatment in men and women who have common lipid abnormalities, but have normal or low concns. of LDL-cholesterol.
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    21. 21
      Walldius, G. The apoB/apoA-I Ratio is a Strong Predictor of Cardiovascular Risk. In Lipoproteins; Sasa, F.; Gerhard, K., Eds.; IntechOpen, 2012, Chapter 5.
      There is no corresponding record for this reference.
    22. 22
      Rössler, T.; Berezhnoy, G.; Singh, Y.; Cannet, C.; Reinsperger, T.; Schäfer, H.; Spraul, M.; Kneilling, M.; Merle, U.; Trautwein, C. Quantitative Serum NMR Spectroscopy Stratifies COVID-19 Patients and Sheds Light on Interfaces of Host Metabolism and the Immune Response with Cytokines and Clinical Parameters. Metabolites 2022, 12, 1277  DOI: 10.3390/metabo12121277
      There is no corresponding record for this reference.
    23. 23
      Kazenwadel, J.; Berezhnoy, G.; Cannet, C.; Schäfer, H.; Geisler, T.; Rohlfing, A.-K.; Gawaz, M.; Merle, U.; Trautwein, C. Stratification of hypertension and SARS-CoV-2 infection by quantitative NMR spectroscopy of human blood serum. Commun. Med. 2023, 3, 145,  DOI: 10.1038/s43856-023-00365-y
      23
      Stratification of hypertension and SARS-CoV-2 infection by quantitative NMR spectroscopy of human blood serum
      Kazenwadel, Jasmin; Berezhnoy, Georgy; Cannet, Claire; Schaefer, Hartmut; Geisler, Tobias; Rohlfing, Anne-Katrin; Gawaz, Meinrad; Merle, Uta; Trautwein, Christoph
      Communications Medicine (2023), 3 (1), 145CODEN: CMOECM; ISSN:2730-664X. (Nature Portfolio)
      Abstr.: Background: Diagnostic approaches like the NMR spectroscopy (NMR) based quantification of metabolites, lipoproteins, and inflammation markers has helped to identify typical alterations in the blood serum of COVID-19 patients. However, confounders such as sex, and comorbidities, which strongly influence the metabolome, were often not considered. Therefore, the aim of this NMR study was to consider sex, as well as arterial hypertension (AHT), when investigating COVID-19-pos. serum samples in a large age-and sex matched cohort. Methods: NMR serum data from 329 COVID-19 patients were compared with 305 healthy controls. 134 COVID-19 patients were affected by AHT. These were analyzed together with NMR data from 58 hypertensives without COVID-19. In addn. to metabolite, lipoprotein, and glycoprotein data from NMR, common lab. parameters were considered. Sex was considered in detail for all comparisons. Results: Here, we show that several differences emerge from previous NMR COVID-19 studies when AHT is considered. Esp., the previously described triglyceride-rich lipoprotein profile is no longer obsd. in COVID-19 patients, nor an increase in ketone bodies. Further alterations are a decrease in glutamine, leucine, isoleucine, and lysine, citric acid, HDL-4 particles, and total cholesterol. Addnl., hypertensive COVID-19 patients show higher inflammatory NMR parameters than normotensive patients. Conclusions: We present a more precise picture of COVID-19 blood serum parameters. Accordingly, considering sex and comorbidities should be included in future metabolomics studies for improved and refined patient stratification. Due to metabolic similarities with other viral infections, these results can be applied to other respiratory diseases in the future.
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    24. 24
      Masuda, R.; Lodge, S.; Whiley, L.; Gray, N.; Lawler, N.; Nitschke, P.; Bong, S.-H.; Kimhofer, T.; Loo, R. L.; Boughton, B.; Zeng, A. X.; Hall, D.; Schaefer, H.; Spraul, M.; Dwivedi, G.; Yeap, B. B.; Diercks, T.; Bernardo-Seisdedos, G.; Mato, J. M.; Lindon, J. C.; Holmes, E.; Millet, O.; Wist, J.; Nicholson, J. K. Exploration of Human Serum Lipoprotein Supramolecular Phospholipids Using Statistical Heterospectroscopy in n-Dimensions (SHY-n): Identification of Potential Cardiovascular Risk Biomarkers Related to SARS-CoV-2 Infection. Anal. Chem. 2022, 94, 4426– 4436,  DOI: 10.1021/acs.analchem.1c05389
      47
      Exploration of Human Serum Lipoprotein Supramolecular Phospholipids Using Statistical Heterospectroscopy in n-Dimensions (SHY-n): Identification of Potential Cardiovascular Risk Biomarkers Related to SARS-CoV-2 Infection
      Masuda, Reika; Lodge, Samantha; Whiley, Luke; Gray, Nicola; Lawler, Nathan; Nitschke, Philipp; Bong, Sze-How; Kimhofer, Torben; Loo, Ruey Leng; Boughton, Berin; Zeng, Annie X.; Hall, Drew; Schaefer, Hartmut; Spraul, Manfred; Dwivedi, Girish; Yeap, Bu B.; Diercks, Tammo; Bernardo-Seisdedos, Ganeko; Mato, Jose M.; Lindon, John C.; Holmes, Elaine; Millet, Oscar; Wist, Julien; Nicholson, Jeremy K.
      Analytical Chemistry (Washington, DC, United States) (2022), 94 (10), 4426-4436CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      SARS-CoV-2 infection causes a significant redn. in lipoprotein-bound serum phospholipids give rise to supramol. phospholipid composite (SPC) signals obsd. in diffusion and relaxation edited 1H NMR spectra. 17708906. To characterize the chem. structural components and compartmental location of SPC and to understand further its possible diagnostic properties, we applied a Statistical HeterospectroscopY in n-dimensions (SHY-n) approach. This involved statistically linking a series of orthogonal measurements made on the same samples, using independent anal. techniques and instruments, to identify the major individual phospholipid components giving rise to the SPC signals. Thus, an integrated model for SARS-CoV-2 pos. and control adults is presented that relates three identified diagnostic subregions of the SPC signal envelope (SPC1, SPC2, and SPC3) generated using diffusion and relaxation edited (DIRE) NMR spectroscopy to lipoprotein and lipid measurements obtained by in vitro diagnostic NMR spectroscopy and ultrahigh-performance liq. chromatog.-tandem mass spectrometry (UHPLC-MS/MS). The SPC signals were then correlated sequentially with (a) total phospholipids in lipoprotein subfractions; (b) apolipoproteins B100, A1, and A2 in different lipoproteins and subcompartments; and (c) MS-measured total serum phosphatidylcholines present in the NMR detection range (i.e., PCs: 16.0,18.2; 18.0,18.1; 18.2,18.2; 16.0,18.1; 16.0,20.4; 18.0,18.2; 18.1,18.2), lysophosphatidylcholines (LPCs: 16.0 and 18.2), and sphingomyelin (SM 22.1). The SPC3/SPC2 ratio correlated strongly (r = 0.86) with the apolipoprotein B100/A1 ratio, a well-established marker of cardiovascular disease risk that is markedly elevated during acute SARS-CoV-2 infection. These data indicate the considerable potential of using a serum SPC measurement as a metric of cardiovascular risk based on a single NMR expt. This is of specific interest in relation to understanding the potential for increased cardiovascular risk in COVID-19 patients and risk persistence in post-acute COVID-19 syndrome (PACS).
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    25. 25
      Mallagaray, A.; Rudolph, L.; Lindloge, M.; Molbitz, J.; Thomsen, H.; Schmelter, F.; Alhabash, M. W.; Abdullah, M. R.; Saraei, R.; Ehlers, M.; Graf, T.; Sina, C.; Petersmann, A.; Nauck, M.; Gunther, U. L. Towards a Precise NMR Quantification of Acute Phase Inflammation Proteins from Human Serum. Angew. Chem. 2023, 62, e202306154  DOI: 10.1002/anie.202306154
      24
      Towards a Precise NMR Quantification of Acute Phase Inflammation Proteins from Human Serum
      Mallagaray, Alvaro; Rudolph, Lorena; Lindloge, Melissa; Molbitz, Jarne; Thomsen, Henrik; Schmelter, Franziska; Alhabash, Mohamad Ward; Abdullah, Mohammed R.; Saraei, Roza; Ehlers, Marc; Graf, Tobias; Sina, Christian; Petersmann, Astrid; Nauck, Matthias; Guenther, Ulrich L.
      Angewandte Chemie, International Edition (2023), 62 (35), e202306154CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      NMR (NMR) spectra of human serum and plasma show, besides metabolites and lipoproteins, two characteristic signals termed GlycA and B arising from the acetyl groups of glycoprotein glycans from acute phase proteins, which constitute good markers for inflammatory processes. Here, we report a comprehensive assignment of glycoprotein glycan NMR signals obsd. in human serum, showing that GlycA and GlycB signals originate from Neu5Ac and GlcNAc moieties from N-glycans, resp. Diffusion-edited NMR expts. demonstrate that signal components can be assocd. with specific acute phase proteins. Conventionally detd. concns. of acute phase glycoproteins correlate well with distinct features in NMR spectra (R2 up to 0.9422, p-value <0.001), allowing the simultaneous quantification of several acute phase inflammation proteins. Overall, a proteo-metabolomics NMR signature of significant diagnostic potential is obtained within 10-20 min acquisition time. This is exemplified in serum samples from COVID-19 and cardiogenic shock patients showing significant changes in several acute phase proteins compared to healthy controls.
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    26. 26
      Anderson, N. L.; Anderson, N. G. The human plasma proteome: history, character, and diagnostic prospects. Mol. Cell. Proteomics 2002, 1, 845– 867,  DOI: 10.1074/mcp.R200007-MCP200
      25
      The human plasma proteome. History, character, and diagnostic prospects
      Anderson, N. Leigh; Anderson, Norman G.
      Molecular and Cellular Proteomics (2002), 1 (11), 845-867CODEN: MCPOBS; ISSN:1535-9476. (American Society for Biochemistry and Molecular Biology, Inc.)
      A review. The human plasma proteome holds the promise of a revolution in disease diagnosis and therapeutic monitoring provided that major challenges in proteomics and related disciplines can be addressed. Plasma is not only the primary clin. specimen but also represents the largest and deepest version of the human proteome present in any sample: in addn. to the classical "plasma proteins," it contains all tissue proteins (as leakage markers) plus very numerous distinct Ig sequences, and it has an extraordinary dynamic range in that more than 10 orders of magnitude in concn. sep. albumin and the rarest proteins now measured clin. Although the restricted dynamic range of conventional proteomic technol. (two-dimensional gels and mass spectrometry) has limited its contribution to the list of 289 proteins (tabulated here) that have been reported in plasma to date, very recent advances in multidimensional survey techniques promise at least double this no. in the near future. Abundant scientific evidence, from proteomics and other disciplines, suggests that among these are proteins whose abundances and structures change in ways indicative of many, if not most, human diseases. Nevertheless, only a handful of proteins are currently used in routine clin. diagnosis, and the rate of introduction of new protein tests approved by the United States Food and Drug Administration (FDA) has paradoxically declined over the last decade to less than one new protein diagnostic marker per yr. We speculate on the reasons behind this large discrepancy between the expectations arising from proteomics and the realities of clin. diagnostics and suggest approaches by which protein-disease assocns. may be more effectively translated into diagnostic tools in the future.
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    27. 27
      Yu, Z.; Kastenmüller, G.; He, Y.; Belcredi, P.; Möller, G.; Prehn, C.; Mendes, J.; Wahl, S.; Roemisch-Margl, W.; Ceglarek, U. Differences between Human Plasma and Serum Metabolite Profiles. PLoS One 2011, 6, e21230  DOI: 10.1371/journal.pone.0021230
      26
      Differences between human plasma and serum metabolite profiles
      Yu, Zhonghao; Kastenmueller, Gabi; He, Ying; Belcredi, Petra; Moeller, Gabriele; Prehn, Cornelia; Mendes, Joaquim; Wahl, Simone; Roemisch-Margl, Werner; Ceglarek, Uta; Polonikov, Alexey; Dahmen, Norbert; Prokisch, Holger; Xie, Lu; Li, Yixue; Wichmann, H.-Erich; Peters, Annette; Kronenberg, Florian; Suhre, Karsten; Adamski, Jerzy; Illig, Thomas; Wang-Sattler, Rui
      PLoS One (2011), 6 (7), e21230CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      Background: Human plasma and serum are widely used matrixes in clin. and biol. studies. However, different collecting procedures and the coagulation cascade influence concns. of both proteins and metabolites in these matrixes. The effects on metabolite concn. profiles have not been fully characterized. Methodol./Principal Findings: We analyzed the concns. of 163 metabolites in plasma and serum samples collected simultaneously from 377 fasting individuals. To ensure data quality, 41 metabolites with low measurement stability were excluded from further anal. In addn., plasma and corresponding serum samples from 83 individuals were re-measured in the same plates and mean correlation coeffs. (r) of all metabolites between the duplicates were 0.83 and 0.80 in plasma and serum, resp., indicating significantly better stability of plasma compared to serum (p = 0.01). Metabolite profiles from plasma and serum were clearly distinct with 104 metabolites showing significantly higher concns. in serum. In particular, 9 metabolites showed relative concn. differences larger than 20%. Despite differences in abs. concn. between the two matrixes, for most metabolites the overall correlation was high (mean r = 0.81 ± 0.10), which reflects a proportional change in concn. Furthermore, when two groups of individuals with different phenotypes were compared with each other using both matrixes, more metabolites with significantly different concns. could be identified in serum than in plasma. For example, when 51 type 2 diabetes (T2D) patients were compared with 326 non-T2D individuals, 15 more significantly different metabolites were found in serum, in addn. to the 25 common to both matrixes. Conclusions/Significance: Our study shows that reproducibility was good in both plasma and serum, and better in plasma. Furthermore, as long as the same blood prepn. procedure is used, either matrix should generate similar results in clin. and biol. studies. The higher metabolite concns. in serum, however, make it possible to provide more sensitive results in biomarker detection.
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    28. 28
      Leeman, M.; Choi, J.; Hansson, S.; Storm, M. U.; Nilsson, L. Proteins and antibodies in serum, plasma, and whole blood-size characterization using asymmetrical flow field-flow fractionation (AF4). Anal. Bioanal. Chem. 2018, 410, 4867– 4873,  DOI: 10.1007/s00216-018-1127-2
      27
      Proteins and antibodies in serum, plasma, and whole blood-size characterization using asymmetrical flow field-flow fractionation (AF4)
      Leeman, Mats; Choi, Jaeyeong; Hansson, Sebastian; Storm, Matilda Ulmius; Nilsson, Lars
      Analytical and Bioanalytical Chemistry (2018), 410 (20), 4867-4873CODEN: ABCNBP; ISSN:1618-2642. (Springer)
      The anal. of aggregates of therapeutic proteins is crucial to ensure efficacy and patient safety. Typically, the anal. was performed in the finished formulation to ensure that aggregates are not present. An important question is, however, what happens to therapeutic proteins, with regard to oligomerization and aggregation, after they have been administered (i.e., in the blood). The sepn. of whole blood, plasma, and serum is shown using asym. flow field-flow fractionation (AF4) with a min. of sample pre-treatment. Furthermore, the anal. and size characterization of a fluorescent antibody in blood plasma using AF4 are demonstrated. The results show the suitability and strength of AF4 for blood anal. and open new important routes for the anal. and characterization of therapeutic proteins in the blood.
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    29. 29
      Collins, L. A.; Olivier, M. Quantitative comparison of lipoprotein fractions derived from human plasma and serum by liquid chromatography-tandem mass spectrometry. Proteome Sci. 2010, 8, 42,  DOI: 10.1186/1477-5956-8-42
      28
      Quantitative comparison of lipoprotein fractions derived from human plasma and serum by liquid chromatography-tandem mass spectrometry
      Collins Lisamarie A; Olivier Michael
      Proteome science (2010), 8 (), 42 ISSN:.
      BACKGROUND: Lipoproteins are complex, globular molecules which play essential roles in the transport and metabolism of cholesterol. Their implication in the development of cardiovascular diseases, such as atherosclerosis, has sustained a great deal of interest in these particles. Their various functions, and their contribution to the development of atherosclerosis, are often attributed to their protein constituents, which vary greatly among the different lipoprotein classes. Recent advances in the field of mass spectrometry have provided insight into the array of proteins associated with low-density lipoproteins (LDLs) and, even more so, with high-density lipoproteins (HDLs). Plasma and serum are the most commonly used samples for the analysis of lipoproteins. Although these lipoprotein sources are unique, it was our goal to determine whether or not their inherent differences would ultimately affect a quantitative analysis of the LDL and HDL proteomes. To this end, we isolated LDL and HDL fractions with fast protein liquid chromatography-size exclusion chromatography (FPLC-SEC) from both human plasma and serum samples from the same individuals. After delipidating these samples, we performed a quantitative proteomic analysis to compare the lipoprotein-associated proteins derived from both plasma and serum. RESULTS: Although the primary differences between the samples are found in fibrinogen proteins which are removed from serum, it of interest to note that, with respect to LDL-associated proteins, apolipoproteinB-100 was found at significantly higher levels in serum samples. Complement component 3 was found at significantly higher levels in serum-derived HDL fractions. Both of these proteins are known LDL- and HDL-associated proteins, respectively. CONCLUSION: Overall, the results from our study indicate that both plasma and serum samples are equally suited for proteomic studies, and provide similar results. These findings are particularly important for studies profiling proteomic differences in lipoprotein particle composition in a variety of disease conditions, including cardiovascular disease.
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    30. 30
      Lippi, G.; Giampaolo, L.; Guidi, G. Effects of anticoagulants on lipoprotein(a) measurements with four commercial assays. Eur. J. Clin. Chem. Clin. Biochem. 1996, 34, 251– 255,  DOI: 10.1515/cclm.1996.34.3.251
      29
      Effects of anticoagulants on lipoprotein(a) measurements with four commercial assays
      Lippi, Giuseppe; Giampaolo, Lidia; Guidi, Giancesare
      European Journal of Clinical Chemistry and Clinical Biochemistry (1996), 34 (3), 251-5CODEN: EJCBEO; ISSN:0939-4974. (de Gruyter)
      Lipoprotein(a) (Lp(a)) levels in plasma are considered an independent risk factor for atherosclerosis at different sites. Although Lp(a) measurements have recently gained interest in clin. labs., several problems are still unresolved. A potential source of pre-anal. variability lies in the treatment of the specimens, since it has been reported that values of several lipid quantities are lower when measured in plasma instead of serum. Lp(a) was measured in serum and in EDTA-treated, heparinized and citrated plasma from 15 healthy volunteers. Four anal. methods were used: two enzyme linked immunosorbent assays [ELISA] based on a polyclonal antiapolipoprotein(a) antibody and a polyclonal anti-apolipoprotein B antibody, resp.; and two immunonephelometric assays [INA] based on a N antiserum to Lp(a) and on three monoclonal antibodies adsorbed on latex particles, resp. The measured Lp(a) values in plasma were lower than those found in serum, in particular for EDTA-treated (anti-apolipoprotein(a) ELISA: p < 0.01, anti-apolipoprotein B ELISA: p < 0.001 and Latex enhanced INA: p < 0.001) and citrated plasma (anti-apolipoprotein(a) ELISA: p < 0.05, anti-apolipoprotein B ELISA: p < 0.001 and INA: p < 0.001). Lp(a) values measured in heparinized plasma were also lower than those found in serum, but the difference was not statistically significant.
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    31. 31
      Loo, R. L.; Lodge, S.; Kimhofer, T.; Bong, S.-H.; Begum, S.; Whiley, L.; Gray, N.; Lindon, J. C.; Nitschke, P.; Lawler, N. G. Quantitative In-Vitro Diagnostic NMR Spectroscopy for Lipoprotein and Metabolite Measurements in Plasma and Serum: Recommendations for Analytical Artifact Minimization with Special Reference to COVID-19/SARS-CoV-2 Samples. J. Proteome Res. 2020, 19, 4428– 4441,  DOI: 10.1021/acs.jproteome.0c00537
      30
      Quantitative In-Vitro Diagnostic NMR Spectroscopy for Lipoprotein and Metabolite Measurements in Plasma and Serum: Recommendations for Analytical Artifact Minimization with Special Reference to COVID-19/SARS-CoV-2 Samples
      Loo, Ruey Leng; Lodge, Samantha; Kimhofer, Torben; Bong, Sze-How; Begum, Sofina; Whiley, Luke; Gray, Nicola; Lindon, John C.; Nitschke, Philipp; Lawler, Nathan G.; Schafer, Hartmut; Spraul, Manfred; Richards, Toby; Nicholson, Jeremy K.; Holmes, Elaine
      Journal of Proteome Research (2020), 19 (11), 4428-4441CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)
      Quant. NMR (NMR) spectroscopy of blood plasma is widely used to investigate perturbed metabolic processes in human diseases. The reliability of biochem. data derived from these measurements is dependent on the quality of the sample collection and exact prepn. and anal. protocols. Here, we describe systematically, the impact of variations in sample collection and prepn. on information recovery from quant. proton (1H) NMR spectroscopy of human blood plasma and serum. The effects of variation of blood collection tube sizes and preservatives, successive freeze-thaw cycles, sample storage at -80°C, and short-term storage at 4 and 20°C on the quant. lipoprotein and metabolite patterns were investigated. Storage of plasma samples at 4°C for up to 48 h, freezing at -80°C and blood sample collection tube choice have few and minor effects on quant. lipoprotein profiles, and even storage at 4°C for up to 168 h caused little information loss. In contrast, the impact of heat-treatment (56°C for 30 min), which has been used for inactivation of SARS-CoV-2 and other viruses, that may be required prior to anal. measurements in low level biosecurity facilities induced marked changes in both lipoprotein and low mol. wt. metabolite profiles. It was conclusively demonstrated that this heat inactivation procedure degrades lipoproteins and changes metabolic information in complex ways. Plasma from control individuals and SARS-CoV-2 infected patients are differentially altered resulting in the creation of artifactual pseudo-biomarkers and destruction of real biomarkers to the extent that data from heat-treated samples are largely uninterpretable. We also present several simple blood sample handling recommendations for optimal NMR-based biomarker discovery investigations in SARS CoV-2 studies and general clin. biomarker research.
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    32. 32
      Vignoli, A.; Tenori, L.; Morsiani, C.; Turano, P.; Capri, M.; Luchinat, C. Serum or Plasma (and Which Plasma), That Is the Question. J. Proteome Res. 2022, 21, 1061– 1072,  DOI: 10.1021/acs.jproteome.1c00935
      31
      Serum or Plasma (and Which Plasma), That Is the Question
      Vignoli, Alessia; Tenori, Leonardo; Morsiani, Cristina; Turano, Paola; Capri, Miriam; Luchinat, Claudio
      Journal of Proteome Research (2022), 21 (4), 1061-1072CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)
      Blood derivs. are the biofluids of choice for metabolomic clin. studies since blood can be collected with low invasiveness and is rich in biol. information. However, the choice of the blood collection tubes has an undeniable impact on the plasma and serum metabolic content. Here, we compared the metabolomic and lipoprotein profiles of blood samples collected at the same time and place from six healthy volunteers but using different collection tubes (each enrolled volunteer provided multiple blood samples at a distance of a few weeks/mo): citrate plasma, EDTA plasma, and serum tubes. All samples were analyzed via NMR spectroscopy. Several metabolites showed statistically significant alterations among the three blood matrixes, and also metabolites' correlations were shown to be affected. The effects of blood collection tubes on the lipoproteins' profiles are relevant too, but less marked. Overcoming the issue assocd. with different blood collection tubes is pivotal to scale metabolomics and lipoprotein anal. at the level of epidemiol. studies based on samples from multicenter cohorts. We propose a statistical soln., based on regression, that is shown to be efficient in reducing the alterations induced by the different collection tubes for both the metabolomic and lipoprotein profiles.
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    33. 33
      Capillary Sampling – Guidelines on Drawing Blood: Best Practices in Phlebotomy WHO: 2010.
      There is no corresponding record for this reference.
    34. 34
      Kupke, I. R.; Zeugner, S.; Gottschalk, A.; Kather, B. Differences in lipid and lipoprotein concentrations of capillary and venous blood samples. Clin. Chim. Acta 1979, 97, 279– 283,  DOI: 10.1016/0009-8981(79)90426-1
      33
      Differences in lipid and lipoprotein concentrations of capillary and venous blood samples
      Kupke, I. R.; Zeugner, S.; Gottschalk, A.; Kather, B.
      Clinica Chimica Acta (1979), 97 (2-3), 279-83CODEN: CCATAR; ISSN:0009-8981.
      The concns. of lipids and lipoproteins measured in capillary blood serum taken from young adults were significantly lower than in venous blood, although they correlated satisfactorily. These differences may reflect differences in the morphol. and hemodynamic conditions existing either in large veins or in the peripheral circulatory system. Thus, venous and capillary blood serum cannot be used interchangeably for these estns.
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    35. 35
      Kupke, I. R.; Kather, B.; Zeugner, S. On the composition of capillary and venous blood serum. Clin. Chim. Acta 1981, 112, 177– 185,  DOI: 10.1016/0009-8981(81)90376-4
      34
      On the composition of capillary and venous blood serum
      Kupke, I. R.; Kather, B.; Zeugner, S.
      Clinica Chimica Acta (1981), 112 (2), 177-85CODEN: CCATAR; ISSN:0009-8981.
      The concns. of various clin.-chem. substances in the capillary and venous blood serum of apparently healthy adults (20-30 yr) were examd. in the fasting state. Total protein, bilirubin, Ca, Na, and C- concns. were significantly lower in capillary than in venous serum. In nonhemolytic capillary serums, the concn. of K was nearly the same as in venous samples. Inorg. P and urea concns. were identical in both specimens. There was a tendency for glucose concns. to be higher in capillary than in venous serum. Capillary and venous blood serum can be used interchangeably only for certain purposes. These results are valid for apparently healthy adults in the fasting state; other population samples remain to be investigated.
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    36. 36
      Sedgwick, M. J.; Morris, J. G.; Nevill, M. E.; Barrett, L. A. Comparison of lipid and lipoprotein concentrations obtained when using capillary and venous plasma. Atherosclerosis 2011, 218, e10  DOI: 10.1016/j.atherosclerosis.2011.07.085
      There is no corresponding record for this reference.
    37. 37
      Lodge, S.; Nitschke, P.; Kimhofer, T.; Wist, J.; Bong, S.-H.; Loo, R. L.; Masuda, R.; Begum, S.; Richards, T.; Lindon, J. C. Diffusion and Relaxation Edited Proton NMR Spectroscopy of Plasma Reveals a High-Fidelity Supramolecular Biomarker Signature of SARS-CoV-2 Infection. Anal. Chem. 2021, 93, 3976– 3986,  DOI: 10.1021/acs.analchem.0c04952
      36
      Diffusion and Relaxation Edited Proton NMR Spectroscopy of Plasma Reveals a High-Fidelity Supramolecular Biomarker Signature of SARS-CoV-2 Infection
      Lodge, Samantha; Nitschke, Philipp; Kimhofer, Torben; Wist, Julien; Bong, Sze-How; Loo, Ruey Leng; Masuda, Reika; Begum, Sofina; Richards, Toby; Lindon, John C.; Bermel, Wolfgang; Reinsperger, Tony; Schaefer, Hartmut; Spraul, Manfred; Holmes, Elaine; Nicholson, Jeremy K.
      Analytical Chemistry (Washington, DC, United States) (2021), 93 (8), 3976-3986CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      We have applied NMR spectroscopy based plasma phenotyping to reveal diagnostic mol. signatures of SARS-CoV-2 infection via combined diffusional and relaxation editing (DIRE). We compared plasma from healthy age-matched controls (n = 26) with SARS-CoV-2 neg. non-hospitalized respiratory patients and hospitalized respiratory patients (n = 23 and 11 resp.) with SARS-CoV-2 rRT-PCR pos. respiratory patients (n = 17, with longitudinal sampling time-points). DIRE data were modelled using principal component anal. and orthogonal projections to latent structures discriminant anal. (O-PLS-DA), with statistical cross-validation indexes indicating excellent model generalization for the classification of SARS-CoV-2 positivity for all comparator groups (area under the receiver operator characteristic curve = 1). DIRE spectra show biomarker signal combinations conferred by differential concns. of metabolites with selected mol. mobility properties. These comprise the following: (a) composite N-acetyl signals from α-1-acid glycoprotein and other glycoproteins (designated GlycA and GlycB) that were elevated in SARS-CoV-2 pos. patients [p = 2.52 x 10-10 (GlycA) and 1.25 x 10-9 (GlycB) vs controls], (b) two diagnostic supramol. phospholipid composite signals that were identified (SPC-A and SPC-B) from the -+N-(CH3)3 choline headgroups of lysophosphatidylcholines carried on plasma glycoproteins and from phospholipids in high-d. lipoprotein subfractions (SPC-A) together with a phospholipid component of low-d. lipoprotein (SPC-B). The integrals of the summed SPC signals (SPCtotal) were reduced in SARS-CoV-2 pos. patients relative to both controls (p = 1.40 x 10-7) and SARS-CoV-2 neg. patients (p = 4.52 x 10-8) but were not significantly different between controls and SARS-CoV-2 neg. patients. The identity of the SPC signal components was detd. using one and two dimensional diffusional, relaxation, and statistical spectroscopic expts. The SPCtotal/GlycA ratios were also significantly different for control vs. SARS-CoV-2 pos. patients (p = 1.23 x 10-10) and for SARS-CoV-2 negatives vs. positives (p = 1.60 x 10-9). Thus, plasma SPCtotal and SPCtotal/GlycA are proposed as sensitive mol. markers for SARS-CoV-2 positivity that could effectively augment current COVID-19 diagnostics and may have value in functional assessment of the disease recovery process in patients with long-term symptoms.
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    38. 38
      Kimhofer, T.; Lodge, S.; Whiley, L.; Gray, N.; Loo, R. L.; Lawler, N. G.; Nitschke, P.; Bong, S.-H.; Morrison, D. L.; Begum, S. Integrative Modeling of Quantitative Plasma Lipoprotein, Metabolic, and Amino Acid Data Reveals a Multiorgan Pathological Signature of SARS-CoV-2 Infection. J. Proteome Res. 2020, 19, 4442– 4454,  DOI: 10.1021/acs.jproteome.0c00519
      37
      Integrative Modeling of Quantitative Plasma Lipoprotein, Metabolic, and Amino Acid Data Reveals a Multiorgan Pathological Signature of SARS-CoV-2 Infection
      Kimhofer, Torben; Lodge, Samantha; Whiley, Luke; Gray, Nicola; Loo, Ruey Leng; Lawler, Nathan G.; Nitschke, Philipp; Bong, Sze-How; Morrison, David L.; Begum, Sofina; Richards, Toby; Yeap, Bu B.; Smith, Chris; Smith, Kenneth G. C.; Holmes, Elaine; Nicholson, Jeremy K.
      Journal of Proteome Research (2020), 19 (11), 4442-4454CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)
      The metabolic effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on human blood plasma were characterized using multiplatform metabolic phenotyping with NMR (NMR) spectroscopy and liq. chromatog.-mass spectrometry (LC-MS). Quant. measurements of lipoprotein subfractions, α-1-acid glycoprotein, glucose, and biogenic amines were made on samples from symptomatic coronavirus disease 19 (COVID-19) patients who had tested pos. for the SARS-CoV-2 virus (n = 17) and from age- and gender-matched controls (n = 25). Data were analyzed using an orthogonal-projections to latent structures (OPLS) method and used to construct an exceptionally strong (AUROC = 1) hybrid NMR-MS model that enabled detailed metabolic discrimination between the groups and their biochem. relationships. Key discriminant metabolites included markers of inflammation including elevated α-1-acid glycoprotein and an increased kynurenine/tryptophan ratio. There was also an abnormal lipoprotein, glucose, and amino acid signature consistent with diabetes and coronary artery disease (low total and HDL Apolipoprotein A1, low HDL triglycerides, high LDL and VLDL triglycerides), plus multiple highly significant amino acid markers of liver dysfunction (including the elevated glutamine/glutamate and Fischer's ratios) that present themselves as part of a distinct SARS-CoV-2 infection pattern. A multivariate training-test set model was validated using independent samples from addnl. SARS-CoV-2 pos. patients and controls. The predictive model showed a sensitivity of 100% for SARS-CoV-2 positivity. The breadth of the disturbed pathways indicates a systemic signature of SARS-CoV-2 positivity that includes elements of liver dysfunction, dyslipidemia, diabetes, and coronary heart disease risk that are consistent with recent reports that COVID-19 is a systemic disease affecting multiple organs and systems. Metabolights study ref.: MTBLS2014.
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    39. 39
      Cutler, D. M. The Costs of Long COVID. JAMA Health Forum. 2022, 3, e221809,  DOI: 10.1001/jamahealthforum.2022.1809
      There is no corresponding record for this reference.
    40. 40
      Masuda, R.; Lodge, S.; Whiley, L.; Gray, N.; Lawler, N.; Nitschke, P.; Bong, S.-H.; Kimhofer, T.; Loo, R. L.; Boughton, B. Exploration of Human Serum Lipoprotein Supramolecular Phospholipids Using Statistical Heterospectroscopy in n-Dimensions (SHYn): Identification of Potential Cardiovascular Risk Biomarkers Related to SARS-CoV-2 Infection. Anal. Chem. 2022, 94, 4426– 4436
      39
      Exploration of Human Serum Lipoprotein Supramolecular Phospholipids Using Statistical Heterospectroscopy in n-Dimensions (SHY-n): Identification of Potential Cardiovascular Risk Biomarkers Related to SARS-CoV-2 Infection
      Masuda, Reika; Lodge, Samantha; Whiley, Luke; Gray, Nicola; Lawler, Nathan; Nitschke, Philipp; Bong, Sze-How; Kimhofer, Torben; Loo, Ruey Leng; Boughton, Berin; Zeng, Annie X.; Hall, Drew; Schaefer, Hartmut; Spraul, Manfred; Dwivedi, Girish; Yeap, Bu B.; Diercks, Tammo; Bernardo-Seisdedos, Ganeko; Mato, Jose M.; Lindon, John C.; Holmes, Elaine; Millet, Oscar; Wist, Julien; Nicholson, Jeremy K.
      Analytical Chemistry (Washington, DC, United States) (2022), 94 (10), 4426-4436CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      SARS-CoV-2 infection causes a significant redn. in lipoprotein-bound serum phospholipids give rise to supramol. phospholipid composite (SPC) signals obsd. in diffusion and relaxation edited 1H NMR spectra. 17708906. To characterize the chem. structural components and compartmental location of SPC and to understand further its possible diagnostic properties, we applied a Statistical HeterospectroscopY in n-dimensions (SHY-n) approach. This involved statistically linking a series of orthogonal measurements made on the same samples, using independent anal. techniques and instruments, to identify the major individual phospholipid components giving rise to the SPC signals. Thus, an integrated model for SARS-CoV-2 pos. and control adults is presented that relates three identified diagnostic subregions of the SPC signal envelope (SPC1, SPC2, and SPC3) generated using diffusion and relaxation edited (DIRE) NMR spectroscopy to lipoprotein and lipid measurements obtained by in vitro diagnostic NMR spectroscopy and ultrahigh-performance liq. chromatog.-tandem mass spectrometry (UHPLC-MS/MS). The SPC signals were then correlated sequentially with (a) total phospholipids in lipoprotein subfractions; (b) apolipoproteins B100, A1, and A2 in different lipoproteins and subcompartments; and (c) MS-measured total serum phosphatidylcholines present in the NMR detection range (i.e., PCs: 16.0,18.2; 18.0,18.1; 18.2,18.2; 16.0,18.1; 16.0,20.4; 18.0,18.2; 18.1,18.2), lysophosphatidylcholines (LPCs: 16.0 and 18.2), and sphingomyelin (SM 22.1). The SPC3/SPC2 ratio correlated strongly (r = 0.86) with the apolipoprotein B100/A1 ratio, a well-established marker of cardiovascular disease risk that is markedly elevated during acute SARS-CoV-2 infection. These data indicate the considerable potential of using a serum SPC measurement as a metric of cardiovascular risk based on a single NMR expt. This is of specific interest in relation to understanding the potential for increased cardiovascular risk in COVID-19 patients and risk persistence in post-acute COVID-19 syndrome (PACS).
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    41. 41
      R: A Language and Environment for Statistical Computing; R Foundation for Statistical Computing: Vienna, Austria, 2022 https://www.R-project.org/.
      There is no corresponding record for this reference.
    42. 42
      Lodge, S.; Lawler, N. G.; Gray, N.; Masuda, R.; Nitschke, P.; Whiley, L.; Bong, S. H.; Yeap, B. B.; Dwivedi, G.; Spraul, M. Integrative Plasma Metabolic and Lipidomic Modelling of SARS-CoV-2 Infection in Relation to Clinical Severity and Early Mortality Prediction. Int. J. Mol. Sci. 2023, 24, 1614  DOI: 10.3390/ijms241411614
      There is no corresponding record for this reference.
    43. 43
      Yuan, L.; Li-Gao, R.; Li-Gao, R.; Verhoeven, A.; van Eyk, H. J.; Bizino, M. B.; Rensen, P. C. N.; Giera, M.; Jazet, I. M.; Lamb, H. J.; Rabelink, T. J. Altered high-density lipoprotein composition is associated with risk for complications in type 2 diabetes mellitus in South Asian descendants: A cross-sectional, case-control study on lipoprotein subclass profiling. Diabetes Obes. Metab. 2023, 25, 2374– 2387,  DOI: 10.1111/dom.15118
      42
      Altered high-density lipoprotein composition is associated with risk for complications in type 2 diabetes mellitus in South Asian descendants: A cross-sectional, case-control study on lipoprotein subclass profiling
      Yuan, Lushun; Li-Gao, Ruifang; Verhoeven, Aswin; van Eyk, Huub J.; Bizino, Maurice B.; Rensen, Patrick C. N.; Giera, Martin; Jazet, Ingrid M.; Lamb, Hildo J.; Rabelink, Ton J.; van den Berg, Bernard M.
      Diabetes, Obesity and Metabolism (2023), 25 (8), 2374-2387CODEN: DOMEF6; ISSN:1462-8902. (Wiley-Blackwell)
      Compn. of high-d. lipoproteins (HDL) is emerging as an important determinant in the development of microvascular complications in type 2 diabetes mellitus (T2DM). Dutch South Asian (DSA) individuals with T2DM display an increased risk of microvascular complications compared with Dutch white Caucasian (DwC) individuals with T2DM. In this study, we aimed to investigate whether changes in HDL compn. assoc. with increased microvascular risk in this ethnic group and lead to new lipoprotein biomarkers. Using 1H NMR spectroscopy and Bruker IVDr Lipoprotein Subclass Anal. (B.I.LISA) software, plasma lipoprotein changes were detd. in 51 healthy individuals (30 DwC, 21 DSA) and 92 individuals with T2DM (45 DwC, 47 DSA) in a cross-sectional, case-control study. Differential HDL subfractions were investigated using multinomial logistic regression analyses, adjusting for possible confounders including BMI and diabetes duration. We identified HDL compositional differences between healthy and diabetic individuals in both ethnic groups. Specifically, levels of apolipoprotein A2 and HDL-4 subfractions were lower in DSA compared with DwC with T2DM. Apolipoprotein A2 and HDL-4 subfractions also neg. correlated with waist circumference, waist-to-hip ratio, Hb A1c, glucose levels and disease duration in DSA with T2DM, and assocd. with increased incidence of microvascular complications. While HDL compn. differed between controls and T2DM in both ethnic groups, the lower levels of lipid content in the smallest HDL subclass (HDL-4) in DSA with T2DM appeared to be more clin. relevant, with higher odds of having diabetes-related pan-microvascular complications such as retinopathy and neuropathy. These typical differences in HDL could be used as ethnicity-specific T2DM biomarkers.
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    44. 44
      Okami, Y.; Chan, Q.; Miura, K.; Kadota, A.; Elliott, P.; Masaki, K.; Okayama, A.; Okuda, N.; Yoshita, K.; Miyagawa, N. Small High-Density Lipoprotein and Omega-3 Fatty Acid Intake Differentiates Japanese and Japanese-Americans: The INTERLIPID Study. J. Atheroscler. Thromb. 2023, 30, 884– 906,  DOI: 10.5551/jat.63762
      43
      Small high-density lipoprotein and omega-3 fatty acid intake differentiates Japanese and Japanese-Americans: the INTERLIPID study
      Okami, Yukiko; Chan, Queenie; Miura, Katsuyuki; Kadota, Aya; Elliott, Paul; Masaki, Kamal; Okayama, Akira; Okuda, Nagako; Yoshita, Katsushi; Miyagawa, Naoko; Okamura, Tomonori; Sakata, Kiyomi; Saitoh, Shigeyuki; Sakurai, Masaru; Nakagawa, Hideaki; Stamler, Jeremiah; Ueshima, Hirotsugu
      Journal of Atherosclerosis and Thrombosis (2023), 30 (8), 884-906CODEN: JATHEH; ISSN:1340-3478. (Japan Atherosclerosis Society)
      To identify the most differentiated serum lipids, esp. concerning particle size and fractions, between Japanese living in Japan and Japanese-Americans in Hawaii, in the absence of possible genetic confounders, and cross-sectionally examine the assocd. modifiable lifestyle factors. Overall, 1,241 (aged 40-59 years) Japanese living in Japan and Japanese-Americans in Hawaii were included. We quantified 130 serum lipid profiles (VLDL 1-5, IDL, LDL 1-6, high-d. lipoprotein [HDL] 1-4, and their subfractions) using Bruker's 1H-NMR spectrometer for the primary outcome. Modifiable lifestyle factors included body mass index (BMI), phys. activity, alc. and smoking habits, and 70 nutrient parameters. We evaluated the different lipids between the groups using partial least squares-discriminant anal. and assocn. between extd. lipids and lifestyle factors using multivariable linear regression anal. Concns. of HDL4, HDL with the smallest particle size, were lower in Japanese than in Japanese-Americans of both sexes. Higher fish-derived omega-3 fatty acid intake and lower alc. intake were assocd. with lower HDL4 concns. A 1% higher kcal intake of total omega-3 fatty acids was assocd. with a 9.8-mg/dL lower HDL4. Fish-derived docosapentaenoic acid, eicosapentaenoic acid, and docosahexaenoic acid intake were inversely assocd. with HDL4 concn. There was no relationship between country, sex, age, or BMI. Japanese and Japanese-Americans can be differentiated based on HDL4 concn. High fish intake among the Japanese may contribute to their lower HDL4 concn. Thus, HDL particle size may be an important clin. marker for coronary artery diseases or a fish consumption biomarker.
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    45. 45
      Stănciulescu, L.-A.; Scafa, A.; Duduianu, C.; Stan, R.; Nicolescu, A.; Deleanu, C.; Dorobantu, M. Lipoprofiling Assessed by NMR Spectroscopy in Patients with Acute Coronary Syndromes: Is There a Need for Fasting Prior to Sampling. Diagnostics 2022, 12, 1675  DOI: 10.3390/diagnostics12071675
      44
      Lipoprofiling Assessed by NMR Spectroscopy in Patients with Acute Coronary Syndromes: Is There a Need for Fasting Prior to Sampling?
      Stanciulescu, Laura-Adina; Scafa, Alexandru; Duduianu, Catalin; Stan, Raluca; Nicolescu, Alina; Deleanu, Calin; Dorobantu, Maria
      Diagnostics (2022), 12 (7), 1675CODEN: DIAGC9; ISSN:2075-4418. (MDPI AG)
      Most patients presenting in an emergency unit with acute coronary syndromes (ACS) (which include non-ST-elevation myocardial infarction (NSTEMI), ST-elevation MI (STEMI), and unstable angina) usually meet at least two cardiovascular risk factors, such as dyslipidemia, arterial hypertension, diabetes mellitus type 2, obesity, history of or current smoking, etc. Most ACS patients suffer from a type of dyslipidemia, and in addn. to this there are ACS patients rushed into the emergency units for which the feeding status is unknown. Thus, we set out to evaluate the effect of fasting on 16 blood metabolite concns. and 114 lipoprotein parameters on one control group and a group of statin-treated ACS patients hospitalized in a cardiovascular emergency unit, using NMR (NMR) spectroscopy. The results indicated trends (in terms of no. of cases, but not necessarily in terms of the magnitude of the effect) for as many as four metabolites and 48 lipoproteins. The effect was defined as a trend for results showing over 70% of the cases from either one or both groups that experienced parameter changes in the same direction (i.e., either increased or decreased). In terms of magnitude, the effect is rather low, leading to the overall conclusion that in cardiovascular (CV) emergency units, the blood samples analyzed in any feeding status would provide close results and very valuable information regarding prognosis and for fast decisions on patient's proper management.
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    46. 46
      Mallol, R.; Rodriguez, M. A.; Brezmes, J.; Masana, L.; Correig, X. Human serum/plasma lipoprotein analysis by NMR: Application to the study of diabetic dyslipidemia. Prog. Nucl. Magn. Reson. Spectrosc. 2013, 70, 1– 24,  DOI: 10.1016/j.pnmrs.2012.09.001
      45
      Human serum/plasma lipoprotein analysis by NMR: Application to the study of diabetic dyslipidemia
      Mallol, Roger; Rodriguez, Miguel Angel; Brezmes, Jesus; Masana, Lluis; Correig, Xavier
      Progress in Nuclear Magnetic Resonance Spectroscopy (2013), 70 (), 1-24CODEN: PNMRAT; ISSN:0079-6565. (Elsevier B.V.)
      A review. This paper discusses the diabetic dyslipidemia on human serum/plasma lipoprotein anal. by NMR. Introduction to lipoproteins and their role in metab. and the clin. importance of lipoprotein characterization for assessing risk factors important for cardiovascular diseases (CVD). Diffusion-edited NMR pulses will be reviewed in detail because they enhance the NMR signal from lipoproteins and eliminate the signal from small metabolites. Three main approaches: (a) curve fitting methods, which are based on a math. deconvolution of the peak to ext. new features from the lipid peak(s) that will then be used as inputs for multivariate anal.; (b) correlation statistical methods, where the points of the original lipid peak envelop are considered to be input features for further processing algorithms since these methods do not deconvolute the peak; and (c) diffusion NMR methods.
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    47. 47
      Fliervoet, L. A. L.; Groenestege, T.; Huisman, W. M. A Comparison of capillary and venous blood sampling for routine coagulation assays. Clin. Biochem. 2022, 104, 30– 35,  DOI: 10.1016/j.clinbiochem.2022.01.010
      46
      Comparison of capillary and venous blood sampling for routine coagulation assays
      Fliervoet, Lies A. L.; Tiel Groenestege, Wouter M.; Huisman, Albert
      Clinical Biochemistry (2022), 104 (), 30-35CODEN: CLBIAS; ISSN:0009-9120. (Elsevier B.V.)
      Capillary blood samples are generally assumed as unsuitable for coagulation testing since it is recognized that contamination with tissue factor and diln. with tissue fluid affects the coagulation assay. However, limited data is available about coagulations assays in which capillary blood sampling is compared to the std. venous blood withdrawal method. The aim of this study was to perform a method comparison between capillary and venous blood sampling for routine coagulation assays. Both venous and capillary (finger stick) blood samples were collected from 188 healthy volunteers and patients. In citrate plasma, International Normalized Ratio (INR), prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen, and D-dimer were measured according to routine protocols using the ACL-TOP 750 LAS (Werfen) coagulation analyzer. Regression anal. was performed and the mean relative difference between capillary and venous sampling was reflected to the total allowable error (TEa). Strong correlations and acceptable variations, using the TEa as decision limit, were found for INR, PT, TT, fibrinogen, and D-dimer between capillary and venous sampling. However, capillary sampling resulted in significant shorter APTT values when using the std. APTT-SP Liq. reagent with a mean bias of -10.4% [95% CI -12.4 to -8.4]. Based on these results, capillary blood sampling proved to be an alternative blood withdrawal method for routine coagulation assays, with the exception of APTT, if a venipuncture is unavailable or undesired.
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