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Our capacity to measure diverse aspects of human biology in vivo has developed rapidly in the past decades, but the rate at which these techniques have generated translatable insights into the biology of psychopathological conditions has lagged far behind. This slow progress is partly due to the poor sensitivity, specificity, and replicability of many findings in the literature, which have in turn been attributed to small effect sizes, small sample sizes, and low statistical power. A commonly proposed solution is to rely on large, consortia-sized samples to facilitate discovery of replicable findings. Here, we argue that increasing sample sizes will have limited impact unless a more fundamental issue is addressed: the precision with which target behavioral phenotypes are measured. We discuss key problems and outline several ways forward, largely centered on the use of appropriate statistical models with deep, transdiagnostic assessment of hierarchically organized and homogeneous psychopathology dimensions across the full range of the severity spectrum. We provide worked examples to demonstrate key problems and potential solutions. Arguably, a precision phenotyping approach can enhance the discovery and replicability of associations between biology and behavior, thereby facilitating insights into the pathophysiological mechanisms underlying psychiatric disorders.

Given the increasing use of threat conditioning and generalization for clinical-translational research efforts, establishing test-retest reliability of these paradigms is necessary. Specifically, it is an empirical question whether the same participant evinces a similar generalization gradient of conditioned responses across two sessions with the identical contingencies and stimuli. Here, 51 human volunteers participated in an identical auditory threat acquisition and generalization protocol at two sessions separated by 9 days. Skin conductance responses (SCR) and trial-by-trial shock risk ratings served as primary dependent measures. We used linear mixed effects modeling to test differential threat responses and generalization gradients, and Generalizability (G) theory coefficients to formally assess test-retest reliability of intra-individual stability and change across time. Results showed largely invariant differential conditioning and generalization gradients across time. G coefficients indicated fair reliability for the majority of acquisition and generalization measures. Our findings support reliability of the threat conditioning and generalization paradigm and highlight their utility for assessments of behavioral interventions in mental health research.

Introduction: Acceptance and commitment therapy (ACT) has a rapidly developing evidence base, with few studies in the developing world or humanitarian context. A recent trial of a guided self-help intervention derived from ACT reported significant positive findings, but the extent to which the central principles of this intervention were maintained and implemented have not been explored.Objective: To examine the role of psychological flexibility as a potential mediator in the relationship between involvement in a guided self-help intervention, Self Help Plus, and psychological distress in a sample of South Sudanese refugee women living in northern Uganda.Methods: We conducted secondary analysis of data from a cluster randomized controlled trial conducted in 2018. We used multilevel mediation modeling to explore the relationship of psychological flexibility, as measured by the Acceptance and Action Questionnaire (AAQ-II), as a mediating factor in the relationship between Self Help Plus involvement and general psychological distress as measured by the Kessler-6 (K6).Results: We found strong multilevel mediation of decreased K6 scores in the treatment group by AAQ-II scores (multilevel b = -3.28). A more pronounced mediation effect was discovered immediately post intervention (b = -1.09) compared to 3-month follow-up (b = -0.84). This is in line with the current literature that demonstrates the role of psychological flexibility as a primary mechanism of change in ACT-based interventions.Conclusions: Psychological flexibility is a contributing component in the theory of change for this ACT-based intervention. Identifying the core components of interventions allows for more effective adaptation and implementation of relevant services, especially in low-resource contexts.

Objective: Generalization of conditioned fear is adaptive in some situations but maladaptive when fear excessively generalizes to innocuous stimuli with incidental resemblance to a genuine threat cue. Recently, empirical interest in fear generalization as a transdiagnostic explanatory mechanism underlying anxiety-related disorders has accelerated. As there are now several studies of fear generalization across multiple types of anxiety-related disorders, the authors conducted a meta-analysis of studies reporting behavioral measures (subjective ratings and psychophysiological indices) of fear generalization in anxiety-related disorder vs. comparison groups.Method: We conducted systematic searches of electronic databases (conducted from January-October 2020) for fear generalization studies involving anxiety-related disorder groups or subclinical analogue groups. A total of 300 records were full-text screened and two unpublished datasets were obtained, yielding 16 studies reporting behavioral fear generalization. Random-effects meta-analytic models and meta-regressions were applied to the behavioral data.Results: Fear generalization was significantly heightened in anxiety-related disorder participants (N=439) relative to comparison participants (N=428). We did not identify any significant clinical, sample, or methodological moderators. Conclusion: Heightened fear generalization is quantitatively supported as distinguishing anxiety-related disorder groups from comparison groups. Evidence suggests this effect is transdiagnostic, relatively robust to experimental or sample parameters, and that generalization paradigms are a well-supported framework for neurobehavioral investigations of learning and emotion in anxiety-related disorders. We discuss these findings in the context of prior meta-analyses and future directions and challenges for the field.