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Metabolomics in epidemiology: sources of variability in metabolite measurements and implications.

ABSTRACT: BACKGROUND:Metabolite levels within an individual vary over time. This within-individual variability, coupled with technical variability, reduces the power for epidemiologic studies to detect associations with disease. Here, the authors assess the variability of a large subset of metabolites and evaluate the implications for epidemiologic studies. METHODS:Using liquid chromatography/mass spectrometry (LC/MS) and gas chromatography-mass spectroscopy (GC/MS) platforms, 385 metabolites were measured in 60 women at baseline and year-one of the Shanghai Physical Activity Study, and observed patterns were confirmed in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening study. RESULTS:Although the authors found high technical reliability (median intraclass correlation = 0.8), reliability over time within an individual was low. Taken together, variability in the assay and variability within the individual accounted for the majority of variability for 64% of metabolites. Given this, a metabolite would need, on average, a relative risk of 3 (comparing upper and lower quartiles of "usual" levels) or 2 (comparing quartiles of observed levels) to be detected in 38%, 74%, and 97% of studies including 500, 1,000, and 5,000 individuals. Age, gender, and fasting status factors, which are often of less interest in epidemiologic studies, were associated with 30%, 67%, and 34% of metabolites, respectively, but the associations were weak and explained only a small proportion of the total metabolite variability. CONCLUSION:Metabolomics will require large, but feasible, sample sizes to detect the moderate effect sizes typical for epidemiologic studies. IMPACT:We offer guidelines for determining the sample sizes needed to conduct metabolomic studies in epidemiology.

SUBMITTER: Sampson JN

PROVIDER: S-EPMC3617076 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Metabolomics in epidemiology: sources of variability in metabolite measurements and implications.

Sampson Joshua N JN Boca Simina M SM Shu Xiao Ou XO Stolzenberg-Solomon Rachael Z RZ Matthews Charles E CE Hsing Ann W AW Tan Yu Ting YT Ji Bu-Tian BT Chow Wong-Ho WH Cai Qiuyin Q Liu Da Ke DK Yang Gong G Xiang Yong Bing YB Zheng Wei W Sinha Rashmi R Cross Amanda J AJ Moore Steven C SC

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20130208 4

<h4>Background</h4>Metabolite levels within an individual vary over time. This within-individual variability, coupled with technical variability, reduces the power for epidemiologic studies to detect associations with disease. Here, the authors assess the variability of a large subset of metabolites and evaluate the implications for epidemiologic studies.<h4>Methods</h4>Using liquid chromatography/mass spectrometry (LC/MS) and gas chromatography-mass spectroscopy (GC/MS) platforms, 385 metabolit ...[more]

PMID: 23396963

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Project description:Freshwater mussels (order Unionida) play a key role in freshwater systems as ecosystem engineers and indicators of aquatic ecosystem health. The fauna is globally imperilled due to a diversity of suspected factors; however, causes for many population declines and mortality events remain unconfirmed due partly to limited health assessment tools. Mussel-monitoring activities often rely on population-level measurements, such as abundance and age structure, which reflect delayed responses to environmental conditions. Measures of organismal health would enable preemptive detection of declining condition before population-level effects manifest. Metabolomic analysis can identify shifts in biochemical pathways in response to stressors and changing environmental conditions; however, interpretation of the results requires information on inherent variability of metabolite concentrations in mussel populations. We targeted metabolites in the haemolymph of two common mussels, Lampsilis cardium and Lampsilis siliquoidea, from three Indiana streams (USA) using ultra-high-performance liquid chromatography combined with quadrupole time-of-flight mass spectroscopy. The influence of species, stream and sex on metabolite variability was examined with distance-based redundancy analysis. Metabolite variability was most influenced by species, followed by site and sex. Inter- and intraspecies metabolite variability among sexes was less distinct than differences among locations. We further categorized metabolites by occurrence and variability in mussel populations. Metabolites with high occurrence (Categories 1 and 2) included those indicative of energy status (catabolism versus anabolism; arginine, proline, carnitine, nicotinic acid, pantothenic acid), oxidative stress (proline, glutamine, glutamate) and protein metabolism (thymidine, cytidine, inosine). Metabolites with lower occurrence (Category 3) are constituents of assorted metabolic pathways and can be important biomarkers with additional temporal sampling to characterize their variability. These data provide a reference for future temporal (before/after) monitoring and for studies of stressor-metabolite linkages in freshwater mussels.

Project description:Polyurethane foam passive air samplers (PUF-PAS) are the most common type of passive air sampler used for a range of semi-volatile organic compounds (SVOCs), including regulated persistent organic pollutants (POPs) and polycyclic aromatic hydrocarbons (PAHs), and emerging contaminants (e.g., novel flame retardants, phthalates, current-use pesticides). Data from PUF-PAS are key indicators of effectiveness of global regulatory actions on SVOCs, such as the Global Monitoring Plan of the Stockholm Convention on Persistent Organic Pollutants. While most PUF-PAS use similar double-dome metal shielding, there is no standardized dome size, shape, or deployment configuration, with many different PUF-PAS designs used in regional and global monitoring. Yet, no information is available on the comparability of data from studies using different PUF-PAS designs. We brought together 12 types of PUF-PAS used by different research groups around the world and deployed them in a multi-part intercomparison to evaluate the variability in reported concentrations introduced by different elements of PAS monitoring. PUF-PAS were deployed for 3 months in outdoor air in Kjeller, Norway in 2015-2016 in three phases to capture (1) the influence of sampler design on data comparability, (2) the influence of analytical variability when samplers are analyzed at different laboratories, and (3) the overall variability in global monitoring data introduced by differences in sampler configurations and analytical methods. Results indicate that while differences in sampler design (in particular, the spacing between the upper and lower sampler bowls) account for up to 50 % differences in masses collected by samplers, the variability introduced by analysis in different laboratories far exceeds this amount, resulting in differences spanning orders of magnitude for POPs and PAHs. The high level of variability due to analysis in different laboratories indicates that current SVOC air sampling data (i.e., not just for PUF-PAS but likely also for active air sampling) are not directly comparable between laboratories/monitoring programs. To support on-going efforts to mobilize more SVOC data to contribute to effectiveness evaluation, intercalibration exercises to account for uncertainties in air sampling, repeated at regular intervals, must be established to ensure analytical comparability and avoid biases in global-scale assessments of SVOCs in air caused by differences in laboratory performance.

Dataset Information

Metabolomics in epidemiology: sources of variability in metabolite measurements and implications.

Publications

Metabolomics in epidemiology: sources of variability in metabolite measurements and implications.

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