Translational phases of evidence in a prognostic biomarker: a systematic review and meta-analysis of natriuretic peptides and the prognosis of stable coronary disease.

CONTEXT: Translational phases of study are important in evaluating whether a prognostic biomarker is likely to have impact on clinical practice but systematic evaluations of such evidence are lacking. OBJECTIVE: To systematically evaluate the clinical usefulness of the published literature on the association of natriuretic peptides (NP) and prognosis in stable coronary disease. DATA SOURCES: MEDLINE and EMBASE until the end of July 2009, without restrictions. STUDY SELECTION: Prospective studies measuring NP in people with stable coronary disease who were followed-up for all cause mortality, coronary or cardiovascular events. DATA EXTRACTION: Two independent reviewers categorised studies according to the American Heart Association phase of study, and extracted data according to the study reporting guidelines from the American Heart Association and REMARK. RESULTS: Systematic review of 19 studies found 17 which were phase 2, reporting an association between NP and events, two phase 3 studies, statistically examining the incremental prognostic value of NP, but no studies assessing whether NP predicted risk sufficiently to change management (phase 4), improve clinical outcomes (phase 5) or cost effectiveness (phase 6). No study referred to a statistical analytic protocol. Meta-analysis of 14 studies, reporting 18,841 patients and 1655 outcome events, found an RR for events of 3.28 (95% CI 2.45 to 4.38) comparing top versus bottom third of NP. This effect was 26% lower among the five studies which adjusted for a priori confounders (age, sex, renal function and left ventricular function) and 38% lower when adjusting for publication bias (Egger's p=0.001). CONCLUSION: The unbiased strength of association of NP with prognosis in stable coronary disease is unclear, and there is a lack of reports of clinically useful measures of prediction and discrimination or studies relating NP levels to clinical decision making. The available literature is confined to early phases and is of limited clinical usefulness.

Evaluating the quality of research into a single prognostic biomarker: a systematic review and meta-analysis of 83 studies of C-reactive protein in stable coronary artery disease.

BACKGROUND: Systematic evaluations of the quality of research on a single prognostic biomarker are rare. We sought to evaluate the quality of prognostic research evidence for the association of C-reactive protein (CRP) with fatal and nonfatal events among patients with stable coronary disease. METHODS AND FINDINGS: We searched MEDLINE (1966 to 2009) and EMBASE (1980 to 2009) and selected prospective studies of patients with stable coronary disease, reporting a relative risk for the association of CRP with death and nonfatal cardiovascular events. We included 83 studies, reporting 61,684 patients and 6,485 outcome events. No study reported a prespecified statistical analysis protocol; only two studies reported the time elapsed (in months or years) between initial presentation of symptomatic coronary disease and inclusion in the study. Studies reported a median of seven items (of 17) from the REMARK reporting guidelines, with no evidence of change over time. The pooled relative risk for the top versus bottom third of CRP distribution was 1.97 (95% confidence interval [CI] 1.78-2.17), with substantial heterogeneity (I(2) = 79.5). Only 13 studies adjusted for conventional risk factors (age, sex, smoking, obesity, diabetes, and low-density lipoprotein [LDL] cholesterol) and these had a relative risk of 1.65 (95% CI 1.39-1.96), I(2) = 33.7. Studies reported ten different ways of comparing CRP values, with weaker relative risks for those based on continuous measures. Adjusting for publication bias (for which there was strong evidence, Egger's p<0.001) using a validated method reduced the relative risk to 1.19 (95% CI 1.13-1.25). Only two studies reported a measure of discrimination (c-statistic). In 20 studies the detection rate for subsequent events could be calculated and was 31% for a 10% false positive rate, and the calculated pooled c-statistic was 0.61 (0.57-0.66). CONCLUSION: Multiple types of reporting bias, and publication bias, make the magnitude of any independent association between CRP and prognosis among patients with stable coronary disease sufficiently uncertain that no clinical practice recommendations can be made. Publication of prespecified statistical analytic protocols and prospective registration of studies, among other measures, might help improve the quality of prognostic biomarker research.

Comparative review of methods for handling drop-out in longitudinal studies.

Longitudinal data analysis is frequently complicated by drop-out. In this paper we consider several methods for dealing with drop-out afflicted data. Along with a general comparison, particular attention is paid to the consequences of model misspecification. The purpose of our approach is two-fold. We first deliberate the form of the drop-out model and compare two alternatives. Furthermore, the extent to which each method is dependent on its core assumptions is assessed through scenarios where one or more such assumptions are compromised. Second, the extent to which we can identify adequacy of model fit is investigated via recently developed diagnostics. These twin targets are pursued via simulation scenarios and application to a schizophrenia trial of over 500 patients with near 50 per cent drop-out.