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Verification of candidate biomarkers relies upon specific, quantitative assays optimized for selective detection of target proteins, and is increasingly viewed as a critical step in the discovery pipeline that bridges unbiased biomarker discovery to preclinical validation. Although individual laboratories have demonstrated that multiple reaction monitoring (MRM) coupled with isotope dilution mass spectrometry can quantify candidate protein biomarkers in plasma, reproducibility and transferability of these assays between laboratories have not been demonstrated. We describe a multilaboratory study to assess reproducibility, recovery, linear dynamic range and limits of detection and quantification of multiplexed, MRM-based assays, conducted by NCI-CPTAC. Using common materials and standardized protocols, we demonstrate that these assays can be highly reproducible within and across laboratories and instrument platforms, and are sensitive to low mug/ml protein concentrations in unfractionated plasma. We provide data and benchmarks against which individual laboratories can compare their performance and evaluate new technologies for biomarker verification in plasma.
Systems biology, i.e. quantitative, postgenomic, postproteomic, dynamic, multiscale physiology, addresses in an integrative, quantitative manner the shockwave of genetic and proteomic information using computer models that may eventually have 10(6) dynamic variables with non-linear interactions. Historically, single biological measurements are made over minutes, suggesting the challenge of specifying 10(6) model parameters. Except for fluorescence and micro-electrode recordings, most cellular measurements have inadequate bandwidth to discern the time course of critical intracellular biochemical events. Micro-array expression profiles of thousands of genes cannot determine quantitative dynamic cellular signalling and metabolic variables. Major gaps must be bridged between the computational vision and experimental reality. The analysis of cellular signalling dynamics and control requires, first, micro- and nano-instruments that measure simultaneously multiple extracellular and intracellular variables with sufficient bandwidth; secondly, the ability to open existing internal control and signalling loops; thirdly, external BioMEMS micro-actuators that provide high bandwidth feedback and externally addressable intracellular nano-actuators; and, fourthly, real-time, closed-loop, single-cell control algorithms. The unravelling of the nested and coupled nature of cellular control loops requires simultaneous recording of multiple single-cell signatures. Externally controlled nano-actuators, needed to effect changes in the biochemical, mechanical and electrical environment both outside and inside the cell, will provide a major impetus for nanoscience.