Gene disease association is often exaggerated, study finds

The link between genetic markers and disease risk is often overstated, say American and Greek researchers. The scientists reviewed the associations identified in highly cited studies, where there was subsequent data available from larger studies and meta-analyses of multiple studies, and found that in the majority of cases the results from the cited studies were found to be exaggerated.

'Many new biomarkers are continuously proposed as potential determinants of disease risk, prognosis, or response to treatment... However, many markers get evaluated only in one or a few studies. Among those evaluated more extensively, few reach clinical practice. This translational attrition requires better study. Are the effect sizes proposed in the literature accurate or overestimated?' say the authors of the study, Professor John Ioannidis from Stanford University, California, and Dr Orestis Panagiotou from the University of Ioannina in Greece.

The associations analysed in the study were selected only if they had been cited more than 400 times in other articles and were themselves published in one of the top 24 most cited biomedical journals. Meta-analyses were then found for the same association. This yielded 35 studies for review, many of which claimed an association to cancer and cardiovascular disease.

Thirty of the 35 highly-cited studies overstated the link to disease when compared to the largest corresponding study on the same association. 'Many investigators are citing the studies that have the most optimistic results', said Professor Ioannidis. 'There's clearly a very strong citation bias'. Twenty-nine of the 35 studies also showed a greater effect than seen in subsequent meta-analyses of multiple studies into the same association.

'Many of these studies were relatively small and among the first to report on the association of interest. Discoveries made in small studies are prone to overestimate or underestimate the actual association... our study documents that results in highly cited biomarker studies often significantly overestimate the findings seen from meta-analyses', said the authors.

Genetic markers that are thought to increase or decrease the risk of a disease can be used by doctors to assess the likelihood of a patient developing the condition and how best to treat them. Therefore, it is important to have reliable data on which to base these decisions. The authors concluded that, 'evidence from multiple studies, in particular large investigations, is necessary to appreciate the discriminating ability of these emerging risk factors. Rapid clinical adoption in the absence of such evidence may lead to wasted resources'.

The study was published in the Journal of the American Medical Association.