Envisioning an improved research strategy for detecting moderators/mediators in intervention studies: A commentary on McClure et al.

The goal of moderator/mediator research in treatment evaluation is to provide guidance to clinicians to choose the best treatment for each patient with a disorder (moderators), and to advise on its optimal protocol or implementation (mediators): personalized/precision medicine. McClure et al. report a systematic review of studies addressing moderators/mediators of the treatment effect of digital interventions for eating disorders, finding no robust moderators or mediators. They attribute this failure to methodological problems, an assessment with which I concur. The focus of this discussion is to clarify which methodological approaches are not likely to be successful, and to envision a research strategy encompassing both hypothesis-generating (exploratory) and hypothesis-testing approaches likely to produce better results not only for eating disorders, but also for all medical treatments.

A diffusion decision model analysis of the cognitive effects of neurofeedback for ADHD.

OBJECTIVE: To examine cognitive effects of neurofeedback (NF) for attention-deficit hyperactivity disorder (ADHD) as a secondary outcome of a randomized clinical trial. METHOD: In a double-blind randomized clinical trial (NCT02251743), 133 7-10-year olds with ADHD received either 38 sessions of NF (n = 78) or control treatment (n = 55) and performed an integrated visual and auditory continuous performance test at baseline, mid- and end-treatment. We used the diffusion decision model to decompose integrated visual and auditory continuous performance test performance at each assessment into cognitive components: efficiency of integrating stimulus information (v), context sensitivity (cv), response cautiousness (a), response bias (z/a), and nondecision time for perceptual encoding and response execution (Ter). Based on prior findings, we tested whether the components known to be deficient improved with NF and explored whether other cognitive components improved using linear mixed modeling. RESULTS: Before NF, children with ADHD showed main deficits in integrating stimulus information (v), which led to less accurate and slower responses than healthy controls (p = .008). The NF group showed significantly more improvement in integrating auditory stimulus information (v) than control treatment (significant group-by-time-by-modality effect: p = .044). CONCLUSIONS: NF seems to improve v, deficient in ADHD. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Cognitive markers for efficacy of neurofeedback for attention-deficit hyperactivity disorder - personalized medicine using computational psychiatry in a randomized clinical trial.

BACKGROUND: Exploring whether cognitive components (identified by baseline cognitive testing and computational modeling) moderate clinical outcome of neurofeedback (NF) for attention-deficit hyperactivity disorder (ADHD). METHOD: 142 children (aged 7-10) with ADHD were randomly assigned to either NF (n = 84) or control treatment (n = 58) in a double-blind clinical trial (NCT02251743). The NF group received live, self-controlled downtraining of electroencephalographic theta/beta ratio power. The control group received identical-appearing reinforcement from prerecorded electroencephalograms from other children. 133 (78 NF, 55 control) children had cognitive processing measured at baseline with the Integrated Visual and Auditory Continuous Performance Test (IVA2-CPT) and were included in this analysis. A diffusion decision model applied to the IVA2-CPT data quantified two latent cognitive components deficient in ADHD: drift rate and drift bias, indexing efficiency and context sensitivity of cognitive processes involving information integration. We explored whether these cognitive components moderated the improvement in parent- and teacher-rated inattention symptoms from baseline to treatment end (primary clinical outcome). RESULTS: Baseline cognitive components reflecting information integration (drift rate, drift bias) moderated the improvement in inattention due to NF vs. control treatment (p = 0.006). Specifically, those with either the most or least severe deficits in these components showed more improvement in parent- and teacher-rated inattention when assigned to NF (Cohen's d = 0.59) than when assigned to control (Cohen's d = -0.21). CONCLUSIONS: Pre-treatment cognitive testing with computational modeling identified children who benefitted more from neurofeedback than control treatment for ADHD.

The future of psychopharmacology: a critical appraisal of ongoing phase 2/3 trials, and of some current trends aiming to de-risk trial programmes of novel agents.

Despite considerable progress in pharmacotherapy over the past seven decades, many mental disorders remain insufficiently treated. This situation is in part due to the limited knowledge of the pathophysiology of these disorders and the lack of biological markers to stratify and individualize patient selection, but also to a still restricted number of mechanisms of action being targeted in monotherapy or combination/augmentation treatment, as well as to a variety of challenges threatening the successful development and testing of new drugs. In this paper, we first provide an overview of the most promising drugs with innovative mechanisms of action that are undergoing phase 2 or 3 testing for schizophrenia, bipolar disorder, major depressive disorder, anxiety and trauma-related disorders, substance use disorders, and dementia. Promising repurposing of established medications for new psychiatric indications, as well as variations in the modulation of dopamine, noradrenaline and serotonin receptor functioning, are also considered. We then critically discuss the clinical trial parameters that need to be considered in depth when developing and testing new pharmacological agents for the treatment of mental disorders. Hurdles and perils threatening success of new drug development and testing include inadequacy and imprecision of inclusion/exclusion criteria and ratings, sub-optimally suited clinical trial participants, multiple factors contributing to a large/increasing placebo effect, and problems with statistical analyses. This information should be considered in order to de-risk trial programmes of novel agents or known agents for novel psychiatric indications, increasing their chances of success.

Wrangling with p-values versus effect sizes to improve medical decision-making: A tutorial.

The most pervasive and damaging myth in clinical research is that the smaller the p-value, the stronger the hypothesis. In reality, the p-value primarily reflects the quality of research design decisions. The most common proposal to avoid misleading conclusions from clinical research requires the appropriate use of effect sizes, but which effect size, used when and how, is an open question. A solution is proposed for perhaps the most common problem in clinical research, the comparison between two populations, for example, comparison of two treatments in a randomized clinical trial or comparison of high risk versus low risk individuals in an epidemiological study: the success rate difference or equivalently the number needed to treat/take (NNT).

Common Types of Gender-Based Microaggressions in Medicine.

PURPOSE: Microaggressions are subtle verbal or nonverbal everyday behaviors that arise from unconscious bias, covert prejudice, or hostility. They may contribute to the persistent disparities faced by women in medicine. In this study, the authors sought to identify common microaggressions experienced by women faculty in medicine and to determine if specific demographic characteristics affect the reported frequencies of these microaggressions. METHOD: The authors used chain referral sampling to collect real-life anecdotes about microaggressions from women faculty across the nation. Thirty-four unique experiences from those reported were identified and scripted then reenacted using professional actors to create 34 videos of the real-life microaggressions and 34 corresponding fictional "control" versions of the same situations. The videos, presented in a random order, were evaluated by faculty from 4 academic medical centers from 2016 to 2018. RESULTS: A total of 124 faculty (79 women, 45 men) participated. Women reported higher frequencies of microaggressions than men in 33 of the 34 videos depicting microaggressions (P value range: < .001 to .042, area under the curve range: 0.60-0.69). No such differences were seen with the control videos. Women identified 21 microaggressions as occurring frequently. No significant differences were found with respect to participants' age, race/ethnicity, academic rank, or years in medicine. Post hoc analyses showed that the microaggressions fell into 6 themes: encountering sexism, encountering pregnancy- and child care-related bias, having abilities underestimated, encountering sexually inappropriate comments, being relegated to mundane tasks, and feeling excluded/marginalized. CONCLUSIONS: Privilege is often invisible to those who have it, whereas bias and discrimination are readily apparent to those who experience it. Knowledge of common microaggressions will allow for targeted individual, interpersonal, and institutional solutions to mitigate disparities in medicine.

"Not just another meta-analysis": Sources of heterogeneity in psychosocial treatment effect on cancer survival.

BACKGROUND: Currently, there are eight meta-analyses that address the question whether psychosocial intervention can prolong survival with widely disparate conclusions. One reason for inconsistent findings may be the methods by which previous meta-analyses were conducted. METHODS: Databases were searched to identify valid randomized controlled trials that compared psychosocial intervention with usual care. Hazard ratios (HRs) and their confidence intervals were pooled to estimate the strength of the treatment effect on survival time, and z-tests were performed to assess possible heterogeneity of effect sizes associated with different patient and treatment characteristics. RESULTS: Twelve trials involving 2439 cancer patients that met screening criteria were included. The overall effect favored the treatment group with a HR of 0.71 (95% Cl 0.58-0.88; P = 0.002). An effect size favoring treatment group was observed in studies sampling lower vs higher percentage of married patients' (NNT = 4.3 vs NNT = 15.4), when Cognitive-Behavioral Therapy was applied at early vs late cancer stage (NNT = 2.3 vs NNT = -28.6), and among patients' older vs younger than 50 (NNT = 4.2 vs NNT = -20.5). CONCLUSIONS: Psychosocial interventions may have an important effect on survival. Reviewed interventions appear to be more effective in unmarried patients, patients who are older, and those with an early cancer stage who attend CBT. Limitations of previous meta-analysis are discussed.

A Three-Step Letter Advance Directive Procedure to Facilitate Patient-Proxy Alignment in Advance Care Planning.

Background: Little is known about the extent of alignment between hematopoietic stem cell transplant (HSCT) patients and their healthcare proxies with respect to advance care planning (ACP). Aim: To determine if a structured three-step process using the letter advance directive (LAD) could (1) allow for the differences in opinion between patient-proxy dyads to surface and (2) help bridge preexisting discordance about specific treatment choices. Design: Blinded to each other, the HSCT patient (LAD-1) and proxy (LAD-2) each completed the LAD (step 1). They unmasked, compared LAD-1 and LAD-2, and discussed their choices (step 2). They completed a final letter directive (LAD-3) by consensus (step 3). Settings/Participants: Convenience sample of eighty dyads (patient and proxy) at a regional HSCT referral center. Results: The mean patient-proxy concordance was 72.9% for the 12 questions in the LAD. Wanting to be pain free at the end of life was the statement with the most amount of agreement (88.75% in LAD-1, 91.25% in LAD-2, and 90% in LAD-3). Patient-proxy dyads had notable discordance related to specific treatments. The highest discordance was related to ventilator support (46.3% of patients refused it, while 58.8% of proxies refused on behalf of the patient). Overall, proxies were more likely than patients to opt in for dialyses and hospice care but more likely to opt out for cardiac resuscitation and sedation to palliate refractory symptoms. On open discussion, patient-proxy discordance mostly resolved in favor of the patient. Conclusions: The ACP process should allow for patient-proxy differences to surface, facilitate a discussion about the granular details with the goal of reaching consensus. Our three-step approach using the LAD is an effective way to identify areas of patient-proxy concordance and discordance about specific treatment preferences. A structured patient-proxy discussion using the LAD helped reconcile discordance and most often in favor of a patient's original wishes.

Common Items on a Bucket List.

BACKGROUND: To provide preference-sensitive care, we propose that clinicians might routinely inquire about their patients' bucket-lists and discuss the impact (if any) of their medical treatments on their life goals. METHODS: This cross-sectional, mixed methods online study explores the concept of the bucket list and seeks to identify common bucket list themes. Data were collected in 2015-2016 through an online survey, which was completed by a total of 3056 participants across the United States. Forty participants who had a bucket list were identified randomly and used as the development cohort: their responses were analyzed qualitatively using grounded theory methods to identify the six key bucket list themes. The responses of the remaining 3016 participants were used for the validation study. The codes identified from the development cohort were validated by analyses of responses from 50 randomly drawn subjects from the validation cohort. All the 3016 validation cohort transcripts were coded for presence or absence of each of the six bucket list themes. RESULTS: Around 91.2% participants had a bucket list. Age and spirituality influence the patient's bucket-list. Participants who reported that faith/religion/spirituality was important to them were most likely (95%) to have a bucket list compared with those who reported it to be unimportant (68.2%), χ2 = 37.67. Six primary themes identified were the desire to travel (78.5%), desire to accomplish a personal goal (78.3%), desire to achieve specific life milestones (51%), desire to spend quality time with friends and family (16.7%), desire to achieve financial stability (24.3%), and desire to do a daring activity (15%). CONCLUSIONS: The bucket list is a simple framework that can be used to engage patients about their healthcare decision making. Knowing a patient's bucket list can aid clinicians in relating each treatment option to its potential impact (if any) on the patient's life and life goals to promote informed decision making.

Depressive symptoms predict head and neck cancer survival: Examining plausible behavioral and biological pathways.

BACKGROUND: Head and neck cancers are associated with high rates of depression, which may increase the risk for poorer immediate and long-term outcomes. Here it was hypothesized that greater depressive symptoms would predict earlier mortality, and behavioral (treatment interruption) and biological (treatment response) mediators were examined. METHODS: Patients (n = 134) reported depressive symptomatology at treatment planning. Clinical data were reviewed at the 2-year follow-up. RESULTS: Greater depressive symptoms were associated with significantly shorter survival (hazard ratio, 0.868; 95% confidence interval [CI], 0.819-0.921; P < .001), higher rates of chemoradiation interruption (odds ratio, 0.865; 95% CI, 0.774-0.966; P = .010), and poorer treatment response (odds ratio, 0.879; 95% CI, 0.803-0.963; P = .005). The poorer treatment response partially explained the depression-survival relation. Other known prognostic indicators did not challenge these results. CONCLUSIONS: Depressive symptoms at the time of treatment planning predict overall 2-year mortality. Effects are partly influenced by the treatment response. Depression screening and intervention may be beneficial. Future studies should examine parallel biological pathways linking depression to cancer survival, including endocrine disruption and inflammation. Cancer 2018;124:1053-60. © 2018 American Cancer Society.

The development of CHAMP: a checklist for the appraisal of moderators and predictors.

BACKGROUND: Personalized healthcare relies on the identification of factors explaining why individuals respond differently to the same intervention. Analyses identifying such factors, so called predictors and moderators, have their own set of assumptions and limitations which, when violated, can result in misleading claims, and incorrect actions. The aim of this study was to develop a checklist for critically appraising the results of predictor and moderator analyses by combining recommendations from published guidelines and experts in the field. METHODS: Candidate criteria for the checklist were retrieved through systematic searches of the literature. These criteria were evaluated for appropriateness using a Delphi procedure. Two Delphi rounds yielded a pilot checklist, which was tested on a set of papers included in a systematic review on reinforced home-based palliative care. The results of the pilot informed a third Delphi round, which served to finalize the checklist. RESULTS: Forty-nine appraisal criteria were identified in the literature. Feedback was obtained from fourteen experts from (bio)statistics, epidemiology and other associated fields elicited via three Delphi rounds. Additional feedback from other researchers was collected in a pilot test. The final version of our checklist included seventeen criteria, covering the design (e.g. a priori plausibility), analysis (e.g. use of interaction tests) and results (e.g. complete reporting) of moderator and predictor analysis, together with the transferability of the results (e.g. clinical importance). There are criteria both for individual papers and for bodies of evidence. CONCLUSIONS: The proposed checklist can be used for critical appraisal of reported moderator and predictor effects, as assessed in randomized or non-randomized studies using individual participant or aggregate data. This checklist is accompanied by a user's guide to facilitate implementation. Its future use across a wide variety of research domains and study types will provide insights about its usability and feasibility.

Statistical Analysis Plan for Stage 1 EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care) Study.

Antidepressant medications are commonly used to treat depression, but only about 30% of patients reach remission with any single first-step antidepressant. If the first-step treatment fails, response and remission rates at subsequent steps are even more limited. The literature on biomarkers for treatment response is largely based on secondary analyses of studies designed to answer primary questions of efficacy, rather than on a planned systematic evaluation of biomarkers for treatment decision. The lack of evidence-based knowledge to guide treatment decisions for patients with depression has lead to the recognition that specially designed studies with the primary objective being to discover biosignatures for optimizing treatment decisions are necessary. Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) is one such discovery study. Stage 1 of EMBARC is a randomized placebo controlled clinical trial of 8 week duration. A wide array of patient characteristics is collected at baseline, including assessments of brain structure, function and connectivity along with electrophysiological, biological, behavioral and clinical features. This paper reports on the data analytic strategy for discovering biosignatures for treatment response based on Stage 1 of EMBARC.

DTI measures identify mild and moderate TBI cases among patients with complex health problems: A receiver operating characteristic analysis of U.S. veterans.

Standard MRI methods are often inadequate for identifying mild traumatic brain injury (TBI). Advances in diffusion tensor imaging now provide potential biomarkers of TBI among white matter fascicles (tracts). However, it is still unclear which tracts are most pertinent to TBI diagnosis. This study ranked fiber tracts on their ability to discriminate patients with and without TBI. We acquired diffusion tensor imaging data from military veterans admitted to a polytrauma clinic (Overall n = 109; Age: M = 47.2, SD = 11.3; Male: 88%; TBI: 67%). TBI diagnosis was based on self-report and neurological examination. Fiber tractography analysis produced 20 fiber tracts per patient. Each tract yielded four clinically relevant measures (fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity). We applied receiver operating characteristic (ROC) analyses to identify the most diagnostic tract for each measure. The analyses produced an optimal cutpoint for each tract. We then used kappa coefficients to rate the agreement of each cutpoint with the neurologist's diagnosis. The tract with the highest kappa was most diagnostic. As a check on the ROC results, we performed a stepwise logistic regression on each measure using all 20 tracts as predictors. We also bootstrapped the ROC analyses to compute the 95% confidence intervals for sensitivity, specificity, and the highest kappa coefficients. The ROC analyses identified two fiber tracts as most diagnostic of TBI: the left cingulum (LCG) and the left inferior fronto-occipital fasciculus (LIF). Like ROC, logistic regression identified LCG as most predictive for the FA measure but identified the right anterior thalamic tract (RAT) for the MD, RD, and AD measures. These findings are potentially relevant to the development of TBI biomarkers. Our methods also demonstrate how ROC analysis may be used to identify clinically relevant variables in the TBI population.

A Randomized Controlled Trial Comparing the Letter Project Advance Directive to Traditional Advance Directive.

BACKGROUND: Simpler alternatives to traditional advance directives that are easy to understand and available in multiple formats and can be initiated by patients and families will help facilitate advance care planning. The goal of this study was to compare the acceptability of the letter advance directive (LAD) to the traditional advance directive (TAD) of the state of California. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: A web-based, randomized controlled trial was conducted, in which the participants were randomized to one of two types of advance directives (ADs): the LAD (intervention) or the TAD (control). Primary outcomes were participant ratings of the ease, value, and their level of comfort in the AD document they completed. RESULTS: A total of 400 participants completed the study, with 216 randomized to the LAD and 184 to the TAD by a computerized algorithm. Overall, participants preferred the LAD to the TAD (success rate difference [SRD] = 0.46, 95th percentile confidence interval [CI]: 0.36-0.56, p < 0.001). The participants felt that, compared to the TAD, the LAD was easier to read and understand (SRD = 0.56, CI: 0.47-0.65, p < 0.001); better reflected what matters most to them (SRD = 0.39, CI: 0.29-0.48, p < 0.001); helped stimulate their thinking about the types of treatments they wanted at the end of life (SRD = 0.32, CI: 0.23-0.42, p < 0.001); allowed them to describe how they made medical decisions in their family (SRD = 0.31, CI: 0.21-0.40, p < 0.001); and could help their doctor(s) (SRD = 0.24, CI: 0.13-0.34, p < 0.001) and their families (SRD = 0.19, CI: 0.08-0.28, p < 0.001) understand their end-of-life treatment preferences. CONCLUSIONS: Patients reported the letter advance directive to be a better alternative to the traditional advance directive form.

Young adult outcomes in the follow-up of the multimodal treatment study of attention-deficit/hyperactivity disorder: symptom persistence, source discrepancy, and height suppression.

BACKGROUND: The Multimodal Treatment Study (MTA) began as a 14-month randomized clinical trial of behavioral and pharmacological treatments of 579 children (7-10 years of age) diagnosed with attention-deficit/hyperactivity disorder (ADHD)-combined type. It transitioned into an observational long-term follow-up of 515 cases consented for continuation and 289 classmates (258 without ADHD) added as a local normative comparison group (LNCG), with assessments 2-16 years after baseline. METHODS: Primary (symptom severity) and secondary (adult height) outcomes in adulthood were specified. Treatment was monitored to age 18, and naturalistic subgroups were formed based on three patterns of long-term use of stimulant medication (Consistent, Inconsistent, and Negligible). For the follow-up, hypothesis-generating analyses were performed on outcomes in early adulthood (at 25 years of age). Planned comparisons were used to estimate ADHD-LNCG differences reflecting persistence of symptoms and naturalistic subgroup differences reflecting benefit (symptom reduction) and cost (height suppression) associated with extended use of medication. RESULTS: For ratings of symptom severity, the ADHD-LNCG comparison was statistically significant for the parent/self-report average (0.51 ± 0.04, p < .0001, d = 1.11), documenting symptom persistence, and for the parent/self-report difference (0.21 ± 0.04, p < .0001, d = .60), documenting source discrepancy, but the comparisons of naturalistic subgroups reflecting medication effects were not significant. For adult height, the ADHD group was 1.29 ± 0.55 cm shorter than the LNCG (p < .01, d = .21), and the comparisons of the naturalistic subgroups were significant: the treated group with the Consistent or Inconsistent pattern was 2.55 ± 0.73 cm shorter than the subgroup with the Negligible pattern (p < .0005, d = .42), and within the treated group, the subgroup with the Consistent pattern was 2.36 ± 1.13 cm shorter than the subgroup with the Inconsistent pattern (p < .04, d = .38). CONCLUSIONS: In the MTA follow-up into adulthood, the ADHD group showed symptom persistence compared to local norms from the LNCG. Within naturalistic subgroups of ADHD cases, extended use of medication was associated with suppression of adult height but not with reduction of symptom severity.

"Evidence"-based medicine in eating disorders research: The problem of "confetti p values".

Eating disorders hold a unique place among mental health disorders, in that salient symptoms can be objectively observed and measured rather than determined only from patient interviews or subjective evaluations. Because of this measurement advantage alone, evidence-based medicine would be expected there to make the most rapid strides. However, conclusions in Eating Disorders research, as in all medical research literature, often continue to be misleading or ambiguous. One major and long-known source of such problems is the misuse and misinterpretation of "statistical significance", with "p values" strewn throughout research papers like so much confetti, a problem that has become systemic, that is, enforced, rather than corrected, by the peer-review system. This discussion attempts to clarify the issues, and to suggest how readers might deal with this issue in processing the research literature.