Finally, it is worth noting that controlling for the intermediary effects of social and academic adjustment at school entry led to negative suppression effects for associations between teacher information sharing and two of the outcomes, general motivation and communication skills.
Again, this could confound findings to the degree that poor dialysis attendance impacted outcomes independent of intermediary effects on IDWG.
Overall, we believe the link between MeHg and MI is plausible, given the range of intermediary effects for which some positive evidence exists and the strength and consistency across the epidemiological studies for MI. Figure 1 illustrates this consistency, showing significant overlap between the effect estimates from the four major studies of MI.
There are a host of intermediary effects and influences that complicate that process, including culture, local and socio-historical contexts, the framing and relevance of the issues as well as perceived benefits and risks related to the research, so these should be noted if possible [ 29, 90].
However, some uncertainty remains as to whether a causal relationship exists because of ambiguity in the specific biological mechanism involved, the small number of epidemiological studies, and inconsistencies in the literature supporting some of the intermediary effects (e.g., BP).
However, of the two, we believe that only MI has sufficient evidence to support its inclusion in a benefits assessment, based on both the current evidence linking MeHg to MI directly and the influence of MeHg on intermediary effects leading to MI.
Some of these effects represent clinical outcomes (e.g., hypertension and MI), whereas others are intermediary effects that may contribute to the progression of heart disease [e.g., oxidative stress, atherosclerosis, and decreased heart rate variability (HRV)].
Therefore it cannot be entirely explained by confounding or intermediary effects.
Criteria in favor of a phase 3 trial include quantitative and qualitative data indicating that the intervention is safe and feasible; data on intermediary outcomes support the effect of the intervention on empowerment of DILs and MILs; and trends in GBV incidence and related health outcomes are in the direction that supports the effect of the intervention.
Third, we test H3, the hypothesized interaction effect of intermediary advice context (advice to participate vs. participation out of the consumers' own interest) with consumers' cost-benefit evaluations for usefulness and enjoyment on consumers' intention to use the health recommendation system.
