Biomedical Engineering Reference
In-Depth Information
intermediate endpoints, which are clinical endpoints that are not the ultimate outcome,
but are nonetheless of real clinical usefulness, for example, exacerbation rate and
ultimate clinical outcomes, which are clinical endpoints reflective of the accumula-
tion of irreversible morbidity and survival. These definitions indicate a clear hier-
archical distinction between biomarkers and surrogate endpoints. While numerous
laboratory biomarkers may be associated with a particular disease state, the term
“surrogate” indicates the ability of a biomarker to provide information about the
clinical prognosis or efficacy of a therapy. The word “surrogate” implies a strong
correlation with a clinical endpoint, but in order to be clinically useful a surrogate
must provide information about prognosis or therapeutic efficacy in a significantly
shorter time than would be needed by following the clinical endpoint.
Historically, successful surrogates have linked effects on biomarkers for single
effects in large populations but this framework needs to be expanded because it
does not recognize multidimensional quality of clinical response and thus conflicts
with current goals for individualized therapy. There is also the need to include pos-
sibility that multiple biomarkers may provide useful information in aggregate.
A biomarker is valid if:
1. It can be measured in a test system with well-established performance
characteristics.
2. Evidence for its clinical significance has been established.
Biomarkers of Cardiovascular Diseases
The major use of cardiac biomarkers until very recently has been the detection of
myocardial infarction (MI). The rationale of using the measurement of a protein in
blood for this purpose is straightforward. The myocyte is the major cell in the heart,
and the heart's purpose is to pump blood. Because myocytes essentially cannot be
regenerated, if heart cells die, then cardiac function has a high probability of being
impaired. When the cell dies, the proteins inside the cell will be released with pro-
teins in the cytoplasm leaving the cell more rapidly than ones in membranes or fixed
cell elements. The most sensitive markers should be those in highest abundance in
the cell, and because the major function of the heart is contraction, the proteins
involved in contraction and producing the energy to support it should be good can-
didates for biomarkers in blood. If such proteins have cardiac-specific forms, then
specificity might be achievable as well as sensitivity. Two classical biomarkers for
MI are serum creatine kinase and troponin. Elevated levels of C-reactive protein
(CRP) are associated with increased risks of ischemic heart disease. One of the
sequelae of MI is congestive heart failure (CHF) and biomarkers for this are also
discussed. Systemic hypertension itself is a marker for heart disease and no separate
markers are listed apart from genetic markers of hypertension. The relative risk of
coronary heart disease is better predicted by two biomarkers than a single biomarker.
More sophisticated multiplex panels have emerged from work with microarrays.
A classification of biomarkers for cardiovascular diseases is shown in Table
4.1
.
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