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.

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).

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.

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.

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.

"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.

Higher vagal activity as related to survival in patients with advanced breast cancer: an analysis of autonomic dysregulation.

OBJECTIVE: High levels of high-frequency heart rate variability (HF-HRV), related to parasympathetic-nervous-system functioning, have been associated with longer survival in patients with myocardial infarction and acute trauma and in patients undergoing palliative care. From animal studies linking higher vagal activity with better immune system functioning and reduced metastases, we hypothesized that higher HF-HRV would predict longer survival in patients with metastatic or recurrent breast cancer (MRBC). METHODS: Eighty-seven patients with MRBC participated in a laboratory task including a 5-minute resting baseline electrocardiogram. HF-HRV was computed as the natural logarithm of the summed power spectral density of R-R intervals (0.15-0.50 Hz). In this secondary analysis of a study testing whether diurnal cortisol slope predicted survival, we tested the association between resting baseline HF-HRV on survival using Cox proportional hazards models. RESULTS: A total of 50 patients died during a median follow-up of 7.99 years. Higher baseline HF-HRV predicted significantly longer survival, with a hazard ratio of 0.75 (95% confidence interval = 0.60-0.92, p = .006). Visceral metastasis status and baseline heart rate were related to both HF-HRV and survival. However, a combination of HF-HRV and heart rate further improved survival prediction, with a hazard ratio of 0.64 (95% confidence interval = 0.48-0.85, p = .002). CONCLUSIONS: Vagal activity of patients with MRBC strongly predicted their survival, extending the known predictive window of HF-HRV in cancer beyond palliative care. Vagal activity can be altered by behavioral, pharmacological, and surgical interventions and may be a promising target for extending life expectancy in patients with metastasizing cancer.

Donepezil treatment in ethnically diverse patients with Alzheimer disease.

OBJECTIVE: To compare the outcome of donepezil treatment in ethnically diverse Alzheimer disease (AD) patients with ethnically diverse AD patients who did not receive donepezil. METHODS: Patients meeting NINCDS-ADRA criteria for probable or possible AD from a consortium of California sites were systematically followed for at least 1 year in this prospective, observational study. Their treatment regimens, including prescription of donepezil, were determined by their individual physician according to his or her usual criteria. Patients self-identified their ethnicity. RESULTS: The 64 ethnically diverse AD patients who completed the study and received donepezil treatment had an average 1-year decline of 2.30 points (standard deviation: 3.9) on the 30-point Mini-Mental State Exam compared with a 1.70-point (standard deviation: 4.2) decline in the 74 ethnically diverse completers who received no donepezil or other anti-AD drugs during the study period. This difference was not statistically significant. The overall Cohen effect size of this treatment-associated difference was estimated at -0.15. After using propensity analyses and other techniques to assess factors that could bias prescribing decisions, the lack of benefits associated with donepezil treatment remained. The lack of donepezil benefits also remained when more traditional analyses were applied to these data. CONCLUSION: Ethnically diverse AD patients in this study apparently did not benefit from 1 year of donepezil treatment. These unpromising results are in contrast to modest benefits of donepezil treatment measured in a directly comparable California study involving white non-Latino AD patients.

Moderators of remission with interpersonal counselling or drug treatment in primary care patients with depression: randomised controlled trial.

BACKGROUND: Despite depressive disorders being very common there has been little research to guide primary care physicians on the choice of treatment for patients with mild to moderate depression. AIMS: To evaluate the efficacy of interpersonal counselling compared with selective serotonin reuptake inhibitors (SSRIs), in primary care attenders with major depression and to identify moderators of treatment outcome. METHOD: A randomised controlled trial in nine centres (DEPICS, Australian New Zealand Clinical Trials Registry number: ACTRN12608000479303). The primary outcome was remission of the depressive episode (defined as a Hamilton Rating Scale for Depression score ≤7 at 2 months). Daily functioning was assessed using the Work and Social Adjustment Scale. Logistic regression models were used to identify moderators of treatment outcome. RESULTS: The percentage of patients who achieved remission at 2 months was significantly higher in the interpersonal counselling group compared with the SSRI group (58.7% v. 45.1%, P = 0.021). Five moderators of treatment outcome were found: depression severity, functional impairment, anxiety comorbidity, previous depressive episodes and smoking habit. CONCLUSIONS: We identified some patient characteristics predicting a differential outcome with pharmacological and psychological interventions. Should our results be confirmed in future studies, these characteristics will help clinicians to define criteria for first-line treatment of depression targeted to patients' characteristics.

The reliability of clinical diagnoses: state of the art.

Reliability of clinical diagnosis is essential for good clinical decision making as well as productive clinical research. The current review emphasizes the distinction between a disorder and a diagnosis and between validity and reliability of diagnoses, and the relationships that exist between them. What is crucial is that reliable diagnoses are essential to establishing valid diagnoses. The present review discusses the theoretical background underlying the evaluation of diagnoses, possible designs of reliability studies, estimation of the reliability coefficient, the standards for assessment of reliability, and strategies for improving reliability without compromising validity.

Loneliness in Seriously Ill Nursing Home Residents During the COVID-19 Pandemic.

Background: Loneliness and social isolation coexist, making it difficult to study each separately. The COVID-19 lockdown provided an unprecedented and ethically viable opportunity to study loneliness in seriously ill nursing home residents under uniformly imposed social isolation conditions. Objective: To understand the phenomenon of loneliness of the seriously ill nursing home patients under a uniform social isolation condition imposed by the COVID-19 pandemic lockdown. Design: Cross-sectional, semi-structured interviews were tape-recorded, transcribed verbatim, and analyzed qualitatively using an inductive thematic analysis. The University of California, Los Angeles (UCLA) Three-Item Loneliness Scale was used to measure loneliness and any relationships between self-reported loneliness and isolation were elucidated. Setting/Participants: Thirty seriously ill nursing home residents living in complete social isolation imposed by the COVID-19 pandemic lockdown. Results: Thematic analysis identified four key themes: (1) Diverse perceptions about the impact of the COVID-19 lockdown, (2) regret over the missed opportunities for spending time with friends and family, (3) using electronic communication to maintain connections with loved ones, and (4) the impact of nursing home staff. In total, 50% of the participants reported feeling socially isolated, 60% patients reported loneliness, and 70% reported being adversely impacted by the lockdown. Patients who felt socially isolated also reported experiencing loneliness (Kendall's Tau = 0.61, 95% confidence interval [CI] = 0.30, 0.89, p < 0.01, large effect size). Persons from communities of color had higher median loneliness scores compared to Non-Hispanic Whites. Participants in the last year of life also reported higher levels of loneliness. Conclusion: A study of loneliness under uniform social isolation conditions in seriously ill nursing home patients showed a high prevalence of loneliness and a strong correlation between self-reported loneliness and social isolation, especially in persons from minority communities and those in the last year of life. In-person support provided by nursing home staff and virtual support from family was helpful to patients.

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).

Toward sound objective evaluation of clinical measures.

The quality of all clinical decision-making, as well as power and precision in clinical research results, depends fundamentally on the quality of the measures used. Yet evaluations of the quality of clinical measures likely to be used either in clinic or research applications are difficult to execute or to critique because the criteria for judging such studies are so ill-defined. Here a set of guidelines is proposed, modeled on CONSORT guidelines for randomized clinical trials, first defining the terms often inconsistently used in the research literature and then identifying certain errors that seem to recur in evaluation studies.

Discovering, comparing, and combining moderators of treatment on outcome after randomized clinical trials: a parametric approach.

No one treatment is likely to affect all patients with a disorder in the same way. A treatment highly effective for some may be ineffective or even harmful for others. Statistically significant or not, the effect sizes of many treatments tend to be small. Consequently, emphasis in clinical research is gradually shifting (1) to increased focus on effect sizes and (2) to discovery and documentation of moderators of treatment effect on outcome in randomized clinical trials, that is, personalized medicine, in which individual differences between patients are explicitly acknowledged. How to test a null hypothesis of moderation of treatment outcome is reasonably well known. The focus here is on how, under parametric assumptions, to define the strength of moderation, that is, a moderator effect size, either for scientific purposes or for assessment of clinical significance, in order to compare moderators and choose among them and to develop a composite moderator, which might more strongly moderate the effect of a treatment on outcome than any single moderator that might ultimately provide guidance for clinicians as to whom to prescribe what treatment.

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.

Stepped care and cognitive-behavioural therapy for bulimia nervosa: randomised trial.

BACKGROUND: This study compared the best available treatment for bulimia nervosa, cognitive-behavioural therapy (CBT) augmented by fluoxetine if indicated, with a stepped-care treatment approach in order to enhance treatment effectiveness. AIMS: To establish the relative effectiveness of these two approaches. METHOD: This was a randomised trial conducted at four clinical centres (Clinicaltrials.gov registration number: NCT00733525). A total of 293 participants with bulimia nervosa were randomised to one of two treatment conditions: manual-based CBT delivered in an individual therapy format involving 20 sessions over 18 weeks and participants who were predicted to be non-responders after 6 sessions of CBT had fluoxetine added to treatment; or a stepped-care approach that began with supervised self-help, with the addition of fluoxetine in participants who were predicted to be non-responders after six sessions, followed by CBT for those who failed to achieve abstinence with self-help and medication management. RESULTS: Both in the intent-to-treat and completer samples, there were no differences between the two treatment conditions in inducing recovery (no binge eating or purging behaviours for 28 days) or remission (no longer meeting DSM-IV criteria). At the end of 1-year follow-up, the stepped-care condition was significantly superior to CBT. CONCLUSIONS: Therapist-assisted self-help was an effective first-level treatment in the stepped-care sequence, and the full sequence was more effective than CBT suggesting that treatment is enhanced with a more individualised approach.

Health-service use in women with binge eating disorders.

OBJECTIVE: To compare health-care utilization between participants who met DSM-IV criteria for binge eating disorder (BED) and those engaged in recurrent binge eating (RBE) and to evaluate whether objective binge eating (OBE) days, a key measurement for diagnosing BED, predicted health-care costs. METHOD: We obtained utilization and cost data from electronic medical records to augment patient reported data for 100 adult female members of a large health maintenance organization who were enrolled in a randomized clinical trial to treat binge eating. RESULTS: Total costs did not differ between the BED and RBE groups (ß = -0.117, z = -0.48, p = .629), nor did the number of OBE days predict total costs (ß = -0.017, z = -1.01, p = .313). DISCUSSION: Findings suggest that the medical impairment, as assessed through health care costs, caused by BED may not be greater than impairment caused by RBE. The current threshold number of two OBE days/week as a criterion for BED may need to be reconsidered.

Screening for binge eating disorders using the Patient Health Questionnaire in a community sample.

OBJECTIVE: To examine the operating characteristics of the Patient Health Questionnaire eating disorder module (PHQ-ED) for identifying bulimia nervosa/binge eating disorder (BN/BED) or recurrent binge eating (RBE) in a community sample and to compare true positive (TP) versus false positive (FP) cases on clinical validators. METHOD: Two hundred and fifty-nine screen-positive individuals and a random sample of 89 screen negative cases completed a diagnostic interview. Sensitivity, specificity, and positive predictive value (PPV) were calculated. TP and FP cases were compared using t-tests and Chi-square tests. RESULTS: The PHQ-ED had high sensitivity (100%) and specificity (92%) for detecting BN/BED or RBE, but PPV was low (10 or 19%). TP and FP cases did not differ significantly on frequency of subjective bulimic episodes, objective overeating, restraint, on BMI, and on self-rated health. DISCUSSION: The PHQ-ED is recommended for use in large populations only in conjunction with follow-up questions to rule out cases without objective bulimic episodes.