Two-step Randomisation: Applying the Results of Small Feasibility Studies of Interventions to Large-scale Mendelian Randomisation Studies to Robustly Infer Causal Effects on Clinical Endpoints

Abstract

Using MR, a genetically instrumented SD increase in pyruvate increased the odds of PCA by 1.29 (1.03, 1.62; p=0.027). ConclusionUsing a two-stage randomization analysis in a feasibility RCT, we found that lycopene lowered levels of pyruvate, which our Mendelian randomization analysis suggests may be causally related to reduced PCA risk. We propose a new two-step randomisation analysis to enhance the value of feasibility studies of novel interventions, with step one being a conventional feasibility randomised controlled trial to assess the effect of the intervention on short-term intermediate biomarkers and step two being Mendelian randomisation analysis using large-scale genome-wide association studies (GWAS) to appraise the causal effect of any intermediates altered by the intervention on long-term clinical outcomes .Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted:

Cancer survivorship, excess body fatness and weight-loss intervention—where are we in 2020?

“…This approach could provide novel insight into the causal effects of an intervention on important intermediate endpoints and possible long-term clinical endpoints (see Figure 2). In this way, Mendelian randomisation can then be used alongside feasibility studies to optimise intervention development and delivery, including more accurate outcome predictions for fully powered conventional randomised controlled trials, 70 as outlined in Figure 2 71 .…”

Applying Mendelian randomization to appraise causality in relationships between nutrition and cancer

“…A two-stage randomisation analysis design has been proposed in which effects of interventions on long-term clinical outcomes are predicted via changes in intermediate biomarkers examined in feasibility trials (i.e., small-scale, preliminary trials which aim to assess the acceptability and viability of interventions). Here, differences in intermediate trait levels across intervention and control arms of a feasibility or early-stage RCT (first stage) are genetically instrumented and then tested for association with a disease outcome of interest using MR (second stage) [ 166 ]. Such an approach permits extension of findings from feasibility trials, which are often unable to establish effects of interventions on clinical endpoints due to their limited duration, to potential downstream effects on cancer risk or progression.…”

Vexed causal inferences in nutritional epidemiology—call for genetic help

“…This ‘two-step randomization’ approach has been performed to investigate potential clinical benefits of lycopene supplementation on prostate cancer risk. 57 First, a feasibility trial of lycopene supplementation 58 was done to determine the systemic metabolic effects of the intervention. Circulating pyruvate concentrations were lowered and the long-term causal effects of this were then investigated in a Mendelian randomization framework, suggesting a lowered prostate cancer risk.…”

“…Circulating pyruvate concentrations were lowered and the long-term causal effects of this were then investigated in a Mendelian randomization framework, suggesting a lowered prostate cancer risk. 57 The logic in this clinical interpretation relies on the assumption that the supplementation effects observed in the short-term intervention step would be sustained long term. On the other hand, the results from the Mendelian randomization with respect to the causal role of circulating pyruvate for prostate cancer are valid regardless, as they indicate the lifelong genetic effects of the metabolite in question.…”