Abstract
BackgroundThe advent of affinity-based proteomics technologies for global protein profiling provides the prospect of finding new molecular biomarkers for common, multifactorial disorders. The molecular phenotypes obtained from studies on such platforms are driven by multiple sources, including genetic, environmental, and experimental components. In characterizing the contribution of different sources of variation to the measured phenotypes, the aim is to facilitate the design and interpretation of future biomedical studies employing exploratory and multiplexed technologies. Thus, biometrical genetic modelling of twin or other family data can be used to decompose the variation underlying a phenotype into biological and experimental components.ResultsUsing antibody suspension bead arrays and antibodies from the Human Protein Atlas, we study unfractionated serum from a longitudinal study on 154 twins. In this study, we provide a detailed description of how the variation in a molecular phenotype in terms of protein profile can be decomposed into familial i.e. genetic and common environmental; individual environmental, short-term biological and experimental components. The results show that across 69 antibodies analyzed in the study, the median proportion of the total variation explained by familial sources is 12% (IQR 1-22%), and the median proportion of the total variation attributable to experimental sources is 63% (IQR 53-72%).ConclusionThe variability analysis of antibody arrays highlights the importance to consider variability components and their relative contributions when designing and evaluating studies for biomarker discoveries with exploratory, high-throughput and multiplexed methods.
Highlights
There is an enormous unmet need for biomarkers to characterize disease type, status, progression, and response to therapy
We have investigated the variance of exploratory affinity arrays using longitudinal twin study
Pre-processing For this study the measured relative quantity of interest is the intensity of fluorescence emitted and measured when antibodies immobilized onto beads capture their target protein from a sample
Summary
Important attributes of discovered biomarkers, in addition to being associated with a disease, are that they can be measured with precision (low variance) and exhibit relatively low amounts of short-term variability relative to the effect size of the difference between healthy and diseased individuals [15]. Plots of the signal intensities of each antibody across the randomized samples (Figure 2A and Additional File 1) show that for some of the antibodies, such as for example apoh-HPA001654, renbp-HPA000428, apohHPA003732 and icam1-HPA004877, signal intensities tended to decrease as intensities were measured from plate well 1 through plate well 96 suggesting an ‘intensitydrift effect’. This could be introduced during sample preparation, modification of the potential binding site during sample labelling, slight bleaching of the fluorophore of the reporter protein, or by the dissociation of antibody-antigen complexes over time the samples are being measured. This shows that for some antibodies including a linear plate specific intensity-drift effect modelled the data
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