The Burden of Proof studies: assessing the evidence of risk

Abstract

Exposure to risks throughout life results in a wide variety of outcomes. Objectively judging the relative impact of these risks on personal and population health is fundamental to individual survival and societal prosperity. Existing mechanisms to quantify and rank the magnitude of these myriad effects and the uncertainty in their estimation are largely subjective, leaving room for interpretation that can fuel academic controversy and add to confusion when communicating risk. We present a new suite of meta-analyses—termed the Burden of Proof studies—designed specifically to help evaluate these methodological issues objectively and quantitatively. Through this data-driven approach that complements existing systems, including GRADE and Cochrane Reviews, we aim to aggregate evidence across multiple studies and enable a quantitative comparison of risk–outcome pairs. We introduce the burden of proof risk function (BPRF), which estimates the level of risk closest to the null hypothesis that is consistent with available data. Here we illustrate the BPRF methodology for the evaluation of four exemplar risk–outcome pairs: smoking and lung cancer, systolic blood pressure and ischemic heart disease, vegetable consumption and ischemic heart disease, and unprocessed red meat consumption and ischemic heart disease. The strength of evidence for each relationship is assessed by computing and summarizing the BPRF, and then translating the summary to a simple star rating. The Burden of Proof methodology provides a consistent way to understand, evaluate and summarize evidence of risk across different risk–outcome pairs, and informs risk analysis conducted as part of the Global Burden of Diseases, Injuries, and Risk Factors Study.

Health effects associated with consumption of unprocessed red meat: a Burden of Proof study

“…We evaluated the relationship between unprocessed red meat consumption and six selected disease outcomes following implementation of a meta-analytic approach 20 . We found that unprocessed red meat intake had weak evidence of an association with increased risk of colorectal cancer, breast cancer, IHD and type 2 diabetes and no evidence of an association with ischemic stroke and hemorrhagic stroke.…”

“…Based upon the star rating categories 20 , unprocessed red meat and colorectal cancer, breast cancer, IHD and type 2 diabetes are all two-star pairs, whereas the two stroke causes are one-star pairs. These star ratings reflect both the magnitude of the RR and its uncertainty and offer policy makers a simple way to conceptualize and compare the evidence for an association between risk and outcome.…”

“…(BPRF) methodology developed by Zheng et al 20 . Specifically, for each risk-outcome pair, we generated a mean risk function by implementing a flexible meta-regression framework that relaxed the conventional assumption of a log-linear dose-response relationship, instead using a data-driven approach to determine the shape of the function using a quadratic spline.…”

“…We computed 95% UIs that account for mean effects uncertainty as well as between-study heterogeneity, adjusting for the number of studies. We used the information to calculate uncertainty inclusive of between-study heterogeneity to generate a BPRF 20 . The BPRF is a conservative risk function (offering an alternative to a mean risk function) that is defined as either the fifth (for harmful risks) or 95th (for protective risks) quantile curve closest to the line of RR equal to one (the null).…”

“…We then converted the BPRF for each risk-outcome pair into a risk-outcome score (ROS) 20 . The ROS summarizes the magnitude and certainty of evidence about a risk or protective factor, with higher positive ROS always corresponding to a stronger relationship and negative ROS corresponding to a failure to reject the null.…”