DISCUSSION
’, allergy, atopic, weakness, eczema
PEANUT ALLERGY, CARD, ALLERGY, ECZEMA, ATOPIC, REGRESSION, EGG ALLERGY
In order to maximize the use of data from the EAT and LEAP studies and assess the efficacy of intervention in important subgroups, we undertook a patient‐level meta‐analysis. The EAT study included participants with varying risk, while LEAP was limited to high‐risk participants. To account for these differences, we included ethnicity, baseline eczema, egg allergy and baseline IgE in our models. A recent systematic review and meta‐analysis concluded that there was moderate evidence to support the early introduction of peanut as a method of reducing peanut allergy prevalence.In summary, the ITT analysis of pooled data showed a 75% reduction in peanut allergy prevalence among children randomized to consume peanut from an early age; moreover, significant reductions were demonstrated in peanut allergy across all eczema severity levels, sensitization groups and ethnic groups. Importantly, a causal inference analysis approach (ATE) demonstrated a significant benefit of the intervention among those without eczema, who make up a majority of children at risk for peanut allergy across the whole population. Moreover, a non‐randomized analysis of age of introduction in the EAT cohort demonstrates an association between earlier age of introduction and increased efficacy (Figure Specialist guidelines often base their recommendations purely on the ‘real world effectiveness’ that intention‐to‐treat analyses provide, whilst ignoring per‐protocol analyses. For example, while the EAT PP analysis showed 100% efficacy (The reluctance to accept per‐protocol analyses as evidence for specialist guidelines has been justified by the concern of introducing bias, since randomization is not always preserved (e.g. more atopic participants could be disproportionately dropped from the intervention arm post‐randomization and thus excluded from per‐protocol analysis, resulting in bias). However, the use of newer causal inference methods have the ability to mitigate this bias with the use of propensity scores, regression adjustment and instrumental variable analysis. It is remarkable that the 2021 Nobel Prize for economics was awarded to David Card, Joshua Angrist and Guido Imbens for, ‘Answering causal questions using observational data’. In this award, Section 1.3 ‘Causal effects in a world with imperfect compliance and individual heterogeneity’, the committee comments that, ‘Imperfect compliance with treatment assignment makes it more difficult to identify the average effect of treatment, in particular when causal effects vary in the population under study … An ITT analysis thus provides an unbiased estimate of the effect of the treatment assignment in the study population, but not the actual causal effect of the treatment itself’.A comparison of naïve PP analyses with the newer causal inference approaches demonstrated consistency of the intervention's efficacy when adhered to. Peanut consumption reduced the risk of PA by 98% (The main strength of our study was the integration and validation of individual‐level data from two large randomized controlled trials (Figure These findings are not without limitations. Firstly, the LEAP and EAT study populations were selected very differently (high and normal risk populations respectively) and followed up to aged 5 and 3 years, respectively. However, the lower risk EAT study is a heterogeneous population with both low‐ and high‐risk participants. A causal inference analysis with adjustment for risk factors such as eczema and egg allergy controls for these differences and shows the intervention to be effective. Secondly, the discrepancy between the PP and ITT results, especially among infants at lower risk of allergy, points to a difference between the intervention's ‘idealized’ efficacy (per‐protocol) and its ‘real world’ effectiveness (ITT).Another weakness of our findings is that the association between age of peanut introduction and prevalence of allergy in the EAT study is, at least partially, an un‐randomized (i.e. observational) comparison. Therefore, this analysis may be confounded by other, unaccounted for factors. A similar analysis was previously performed in the LEAP population.The results of this pooled analysis provide new evidence for the efficacy of early introduction of peanut in children with all degrees of eczema severity and moreover demonstrates efficacy in those without eczema. Moreover, this efficacy is demonstrated irrespective of ethnic group, peanut sensitization status and presence of egg allergy. These results suggest that recommending early consumption of peanut as a prevention strategy be broadly applied to the entire population, rather than targeting selected higher risk groups. Moreover, our results point to increased efficacy of the intervention with an age of introduction below 6 months, calling into question recommendations for exclusive breastfeeding during the first 6 months of life in resource‐rich regions. Utilizing individual‐level data from all RCTs of peanut introduction to date, these new analyses thus strengthen the evidence that underlie the EAACI guidelines recommending early introduction of peanut to the general population.