Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality in the United States.1 Primary prevention and secondary prevention of CVD are public health priorities.2 Substantial data indicate that CVD is a life course disease that begins with the evolution of risk factors that in turn contribute to the development of subclinical atherosclerosis.3,4 Subclinical disease culminates in overt CVD.5,6 The onset of CVD itself portends an adverse prognosis with greater risk of recurrent events, morbidity, and mortality.7,8 It is also increasingly clear that although clinical assessment is the keystone of patient management, such evaluation has its limitations.9–12 Clinicians have used additional tools to aid clinical assessment and to enhance their ability to identify the “vulnerable” patient at risk for CVD, as suggested by a recent National Institutes of Health (NIH) panel.13,14 Biomarkers are one such tool to better identify high-risk individuals, to diagnose disease conditions promptly and accurately, and to effectively prognosticate and treat patients with disease. This review provides an overview of the molecular basis of biomarker discovery and selection and the practical considerations that are a prerequisite to their clinical use.

The term biomarker (biological marker) was introduced in 1989 as a Medical Subject Heading (MeSH) term: “measurable and quantifiable biological parameters (eg, specific enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances) which serve as indices for health- and physiology-related assessments, such as disease risk, psychiatric disorders, environmental exposure and its effects, disease diagnosis, metabolic processes, substance abuse, pregnancy, cell line development, epidemiologic studies, etc.” In 2001, an NIH working group standardized the definition of a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” …

Biomarkers of cardiovascular disease: molecular basis and practical considerations.

Background: Analysis of proteins has been an integral part of the field of clinical chemistry for decades. Recent advances in technology and complete identification of the human genome sequence have opened up new opportunities for analysis of proteins for clinical diagnostic purposes.

Methods: Content of a recent conference of proteomics is summarized.

Results: New analytical methods allow the simultaneous analysis of a large number of proteins in biological fluids such as serum and plasma, offering partial views of the complete set of proteins or proteome. Plasma presents many analytical challenges, such as the complexity of components, predominance of a few major components, and the large concentration range of components, but the number of proteins that can be detected in plasma has expanded dramatically from hundreds to thousands. At the same time, there is increased capability to detect structural variations of proteins. Recent studies also identified the presence of complex sets of small protein fragments in plasma. This set of protein fragments, the fragmentome or peptidome, is potentially a rich source of information about physiologic and disease processes.

Conclusions: Advances in proteomics offer great promise for the discovery of markers that might serve as the basis for new clinical laboratory tests. There are many challenges, however, in the translation of newly discovered markers into clinical laboratory tests.

Proteomics: A New Diagnostic Frontier

As a part of ongoing efforts of the NCI-FDA Interagency Oncology Task Force subcommittee on molecular diagnostics, members of the Clinical Proteomic Technology Assessment for Cancer program of the National Cancer Institute have submitted 2 protein-based multiplex assay descriptions to the Office of In Vitro Diagnostic Device Evaluation and Safety, US Food and Drug Administration The objective was to evaluate the analytical measurement criteria and studies needed to validate protein-based multiplex assays Each submission described a different protein-based platform: a multiplex immunoaffinity mass spectrometry platform for protein quantification, and an immunological array platform quantifying glycoprotein isoforms Submissions provided a mutually beneficial way for members of the proteomics and regulatory communities to identify the analytical issues that the field should address when developing protein-based multiplex clinical assays

Protein-Based Multiplex Assays: Mock Presubmissions to the US Food and Drug Administration

Toxicoproteomics uses the discovery potential of proteomics in toxicology research by applying global protein measurement technologies to biofluids and tissues after host exposure to injurious agents. Toxicoproteomic studies thus far have focused on protein profiling of major organs and biofluids such as liver and blood in preclinical species exposed to model toxicants. The slow pace of discovery for new biomarkers, toxicity signatures and mechanistic insights is partially due to the limited proteome coverage derived from analysis of native organs, tissues and body fluids by traditional proteomic platforms. Improved toxicoproteomic analysis would result by combining higher data density LC-MS/MS platforms with stable isotope labelled peptides and parallel use of complementary platforms. Study designs that remove abundant proteins from biofluids, enrich subcellular structures and include cell specific isolation from heterogeneous tissues would greatly increase differential expression capabilities. By leveraging resources from immunology, cell biology and nutrition research communities, toxicoproteomics could make particular contributions in three inter-related areas to advance mechanistic insights and biomarker development: the plasma proteome and circulating microparticles, the adductome and idiosyncratic toxicity.

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The plasma proteome, adductome and idiosyncratic toxicity in toxicoproteomics research.

Quality Assurance of RNA Expression Profiling in Clinical Laboratories

FDA oversight of medical devices, including in vitro diagnostic devices (IVDs or laboratory tests), in the United States was a direct result of the passage of the Medical Device Amendments of 1976. This law introduced a series of general controls for medical devices including registration and listing, requirements for production using good manufacturing practices, and requirements for post-market reporting of device failures. This produced for the first time a menu of laboratory tests on the market, a system to ensure these were produced consistently over time, and a mechanism for FDA to identify problems with device use and to work with companies to ensure corrective action. This law also introduced the requirement for premarket review of new versions of old devices and of fundamentally new medical devices.

Introduction to the Food and Drug Administration (FDA) regulatory process.

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Introduction to the Food and Drug Administration (FDA) regulatory process.