Many nonnormalities, one simulation: Do different data generation algorithms affect study results?

Monte Carlo simulation studies are among the primary scientific outputs contributed by methodologists, guiding application of various statistical tools in practice. Although methodological researchers routinely extend simulation study findings through follow-up work, few studies are ever replicated. Simulation studies are susceptible to factors that can contribute to replicability failures, however. This paper sought to conduct a meta-scientific study by replicating one highly cited simulation study (Curran et al., Psychological Methods, 1, 16-29, 1996) that investigated the robustness of normal theory maximum likelihood (ML)-based chi-square fit statistics under multivariate nonnormality. We further examined the generalizability of the original study findings across different nonnormal data generation algorithms. Our replication results were generally consistent with original findings, but we discerned several differences. Our generalizability results were more mixed. Only two results observed under the original data generation algorithm held completely across other algorithms examined. One of the most striking findings we observed was that results associated with the independent generator (IG) data generation algorithm vastly differed from other procedures examined and suggested that ML was robust to nonnormality for the particular factor model used in the simulation. Findings point to the reality that extant methodological recommendations may not be universally valid in contexts where multiple data generation algorithms exist for a given data characteristic. We recommend that researchers consider multiple approaches to generating a specific data or model characteristic (when more than one is available) to optimize the generalizability of simulation results.

The role of frailty in the association between depression and fall risk among older adults.

OBJECTIVES: Although there is a recognized association between depression and greater fall risk among older adults, the mechanisms explaining this association are unclear. This study evaluated the role of frailty, a common geriatric syndrome, in determining greater risk of falls among older adults with depression. METHOD: We used longitudinal data from three biennial waves of the Health and Retirement Study (HRS; 2010-2014). The sample included community-dwelling survey respondents age ≥ 65 who participated in objective physiological measures. Major Depression (MD) was measured using Composite International Diagnostic Interview for depression short form. Frailty was measured using criteria outlined in the frailty phenotype model. Causal mediation analysis was used to differentiate the direct effect of depression and indirect effect mediated by frailty on falls, fall injuries, and multiple falls. RESULTS: Major depression was associated with significantly greater odds of experiencing a fall (OR: 1.91; 95% CI: 1.31, 2.77), fall injury (OR: 1.86; 95% CI: 1.17, 2.95), and multiple falls (OR: 2.26; 95% CI: 1.52, 3.37) over a two-year period. Frailty was a significant mediator of the effects of depression on falls and multiple falls, accounting for approximately 18.9% and 21.3% of the total effects, respectively. We found no evidence of depression-frailty interaction. Sensitivity analyses showed that results were robust to unmeasured confounding and alternative operationalizations of depression. CONCLUSION: Frailty explains a significant proportion of increased likelihood of falls among older adults with depression. Treatment and management of frailty symptoms may be an important components of fall prevention among older adults with depression.

A Guideline for Reporting Mediation Analyses of Randomized Trials and Observational Studies: The AGReMA Statement.

Importance: Mediation analyses of randomized trials and observational studies can generate evidence about the mechanisms by which interventions and exposures may influence health outcomes. Publications of mediation analyses are increasing, but the quality of their reporting is suboptimal. Objective: To develop international, consensus-based guidance for the reporting of mediation analyses of randomized trials and observational studies (A Guideline for Reporting Mediation Analyses; AGReMA). Design, Setting, and Participants: The AGReMA statement was developed using the Enhancing Quality and Transparency of Health Research (EQUATOR) methodological framework for developing reporting guidelines. The guideline development process included (1) an overview of systematic reviews to assess the need for a reporting guideline; (2) review of systematic reviews of relevant evidence on reporting mediation analyses; (3) conducting a Delphi survey with panel members that included methodologists, statisticians, clinical trialists, epidemiologists, psychologists, applied clinical researchers, clinicians, implementation scientists, evidence synthesis experts, representatives from the EQUATOR Network, and journal editors (n = 19; June-November 2019); (4) having a consensus meeting (n = 15; April 28-29, 2020); and (5) conducting a 4-week external review and pilot test that included methodologists and potential users of AGReMA (n = 21; November 2020). Results: A previously reported overview of 54 systematic reviews of mediation studies demonstrated the need for a reporting guideline. Thirty-three potential reporting items were identified from 3 systematic reviews of mediation studies. Over 3 rounds, the Delphi panelists ranked the importance of these items, provided 60 qualitative comments for item refinement and prioritization, and suggested new items for consideration. All items were reviewed during a 2-day consensus meeting and participants agreed on a 25-item AGReMA statement for studies in which mediation analyses are the primary focus and a 9-item short-form AGReMA statement for studies in which mediation analyses are a secondary focus. These checklists were externally reviewed and pilot tested by 21 expert methodologists and potential users, which led to minor adjustments and consolidation of the checklists. Conclusions and Relevance: The AGReMA statement provides recommendations for reporting primary and secondary mediation analyses of randomized trials and observational studies. Improved reporting of studies that use mediation analyses could facilitate peer review and help produce publications that are complete, accurate, transparent, and reproducible.

Assessing Acceptability of the Term: "Psychopathology" Among Youth Aged 18-25.

A prevailing model for mental health care for youth and families is to provide services within a "psychopathology" focused framework. This approach can compound problems for youth by imparting negative labels on them, and may be associated with iatrogenic impacts of interventions (e.g., stigmatization, lowered self-efficacy, dependency). This study assessed perceptions of the term "psychopathology" among 486 youth aged 18-25, with 39% of these youth receiving prior mental health services. Results indicated statistically significant differences in perception of the term, with youth who had received mental health services perceiving it more negatively than youth who had not. Findings suggest receipt of mental health services among young people may sensitize them to negative aspects of the term psychopathology, indicating the need for caution in using this term and other terms that may have negative impacts on mental health service use among youth.

Biobehavioral composite of social aspects of anxiety in young adults with fragile X syndrome contrasted to autism spectrum disorder.

Social anxiety is a common disorder that has negative impacts across multiple domains of function. Several clinical groups are at elevated risk for social anxiety, including those with fragile X syndrome and those with autism spectrum disorder. Measuring social anxiety in these clinical subgroups is fraught with challenge, however, given the complexity of social anxiety and measurement limitations that are particularly acute in persons with neurodevelopmental disorders. The over-arching aim of this study was to contribute to our understanding of the nature of social anxiety in fragile X syndrome and its association with autism spectrum disorder. To address this aim, we created a multi-faceted composite representing behavioral and biological aspects of social anxiety and examined differences in two adolescent and young adult-aged groups: 59 males with fragile X syndrome and 18 males with autism spectrum disorder. Results indicated a lower score on the multivariate composite for the males with fragile X syndrome relative to autism spectrum disorder but with evidence that traits of autism and social anxiety overlap. We conclude that measuring anxiety and autism traits in fragile X syndrome and autism spectrum disorder is complex with features that overlap and interact in a dynamic manner.

The influence of race and comorbidity on the timely initiation of antiretroviral therapy among older persons living with HIV/AIDS.

OBJECTIVES: We examined whether the timely initiation of antiretroviral therapy (ART) differed by race and comorbidity among older (≥ 50 years) people living with HIV/AIDS (PLWHA). METHODS: We conducted frequency and descriptive statistics analysis to characterize our sample, which we drew from 2005-2007 Medicaid claims data from 14 states. We employed univariate and multivariable Cox regression analyses to evaluate the relationship between race, comorbidity, and timely ART initiation (≤ 90 days post-HIV/AIDS diagnosis). RESULTS: Approximately half of the participants did not commence ART promptly. After we adjusted for covariates, we found that older PLWHA who reported a comorbidity were 40% (95% confidence interval = 0.26, 0.61) as likely to commence ART promptly. We found no racial differences in the timely initiation of ART among older PLWHA. CONCLUSIONS: Comorbidities affect timely ART initiation in older PLWHA. Older PLWHA may benefit from integrating and coordinating HIV care with care for other comorbidities and the development of ART treatment guidelines specific to older PLWHA. Consistent Medicaid coverage helps ensure consistent access to HIV treatment and care and may eliminate racial disparities in timely ART initiation among older PLWHA.

Social Communication Delay in an Unbiased Sample of Preschoolers With the FMR1 Premutation.

PURPOSE: The Fragile X Messenger Ribonucleoprotein-1 (FMR1) premutation (FXpm) is a genetic variant that is common in the general population and is associated with health symptoms and disease in adulthood. However, poor understanding of the clinical phenotype during childhood has hindered the development of clinical practice guidelines for screening and intervention. Given that social communication difficulties have been widely documented in adults with the FXpm and are linked with reduced psychosocial functioning, the present study aimed to characterize the communication profile of the FXpm during early childhood. METHOD: Eighteen children with the FXpm who were identified through cascade testing (89%) or screening at birth (11%) were compared to 21 matched typically developing children, aged 2-4 years. Participants completed standardized assessments of language (Mullen Scales of Early Learning) and adaptive communication (Vineland Adaptive Behavior Scales-II). Social communication was rated from seminaturalistic interaction samples using the Brief Observation of Social Communication Change. RESULTS: Children with the FXpm showed delayed social communication development, with the magnitude of group differences highlighting social communication as a feature that distinguishes children with the FXpm from their peers (p = .046, ηp2 = .12). The groups did not differ on the standardized language and adaptive communication measures (ps > .297, ηp2s < .03). CONCLUSIONS: Early screening and treatment of social communication delays may be key to optimizing outcomes for children with the FXpm. Further research is needed to replicate findings in a larger sample, delineate the trajectory and consequences of social communication difficulties across the life span in the FXpm, and determine the potential epidemiological significance of FMR1 as a mediator of developmental communication differences within the general population.

A Bayesian Approach for Estimating Mediation Effects with Missing Data.

Methodologists have developed mediation analysis techniques for a broad range of substantive applications, yet methods for estimating mediating mechanisms with missing data have been understudied. This study outlined a general Bayesian missing data handling approach that can accommodate mediation analyses with any number of manifest variables. Computer simulation studies showed that the Bayesian approach produced frequentist coverage rates and power estimates that were comparable to those of maximum likelihood with the bias-corrected bootstrap. We share a SAS macro that implements Bayesian estimation and use two data analysis examples to demonstrate its use.

One step at a time: A statistical approach for distinguishing mediators, confounders, and colliders using direction dependence analysis.

In observational data, understanding the causal link when estimating the causal effect of an independent variable (x) on a dependent variable (y) often requires researchers to identify the role of a third variable in the x → y relationship. Mediation, confounding, and colliding are three key third-variable effects that yield different theoretical and methodological implications for drawing causal conclusions. Commonly used covariance-based statistical methods, such as linear regression and structural equation modeling, cannot distinguish these effects in practice, however. In this study, we introduce a statistical approach for distinguishing mediators, confounders, colliders, and potential M-bias structures that uses higher-order moment information from the data. We propose a two-step procedure that uses the Hilbert-Schmidt independence criterion within the direction dependence analysis framework. Results from Monte Carlo simulations show that our proposed approach accurately recovers the true data-generating process of the third variable. We provide an empirical example to demonstrate the application of our proposed approach in psychological research. Finally, we discuss implications and future directions of our work. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Design, analysis, and interpretation of treatment response heterogeneity in personalized nutrition and obesity treatment research.

It is increasingly assumed that there is no one-size-fits-all approach to dietary recommendations for the management and treatment of chronic diseases such as obesity. This phenomenon that not all individuals respond uniformly to a given treatment has become an area of research interest given the rise of personalized and precision medicine. To conduct, interpret, and disseminate this research rigorously and with scientific accuracy, however, requires an understanding of treatment response heterogeneity. Here, we define treatment response heterogeneity as it relates to clinical trials, provide statistical guidance for measuring treatment response heterogeneity, and highlight study designs that can quantify treatment response heterogeneity in nutrition and obesity research. Our goal is to educate nutrition and obesity researchers in how to correctly identify and consider treatment response heterogeneity when analyzing data and interpreting results, leading to rigorous and accurate advancements in the field of personalized medicine.

Future Orientation Among Children Affected by Parental HIV in China: An Exploratory Analysis of Complex Interactions.

We utilized an exploratory analytic approach to examine predictors of children's future beliefs, an internal asset associated with resilience among children affected by HIV, with emphasis on complex interactions among multisystem factors. Children (N = 1221) affected by parental HIV in China reported on psychosocial functioning, as well as internal, familial, and community resilience assets. Exploratory data analysis was conducted using a binary segmentation program. Six binary splits on predictors accounted for 22.78% of the variance in future expectation, suggesting interactions between children's perceived control of their future, loneliness, caregiver trust, and social support. Four binary splits accounted for 23.15% of the variance in future orientation, suggesting multiway interactions between control of the future, loneliness, social support, and perceived stigma. Findings suggest combinations of resilience factors are associated with children's positive future beliefs. Implications for screening, prevention, and intervention among Chinese children affected by parental HIV are discussed.

An overview of the Connect through PLAY trial to increase physical activity in underserved adolescents.

BACKGROUND: The Connect through Positive Leisure Activities for Youth (Connect through PLAY) trial is a prospective, randomized controlled trial implemented within pre-existing afterschool programs (ASPs) comparing a staff-based social development physical activity (PA) program to a health curriculum active control. The efficacy trial aims to improve staff capacity for implementing effective physical activity (PA) programming within ASPs serving underserved youth (minority, low-income) through enhancing the influence of ASP staff as key change agents and addressing the social development needs of adolescents. DESIGN AND SETTING: The 5-year cluster randomized trial will involve 30 ASPs that are randomized to either the Connect through PLAY intervention or the active health curriculum control. INTERVENTION: The Connect through PLAY intervention employs a novel theoretical framework that targets three key social mechanisms for increased and sustained PA of staff and youth including youth-peer connections/friendships, group belonging, and staff-youth connections. All components of the intervention are designed to improve staff capacity for facilitating a PA context that supports these social mechanisms and increases the influence of ASP staff as positive PA role models and agents of change. Compared to control sites, ASPs receiving Connect through PLAY are expected to show greater improvements from baseline to post- and 6-month follow-up on youth PA, staff PA, and social mechanisms. IMPLICATIONS: The results of the Connect through PLAY trial will demonstrate the efficacy of the intervention and will assist in developing a model of training, motivating, and empowering ASP staff to address social mechanisms that promote youth PA.

Low normal FMR1 genotype in older adult women: Psychological well-being and motor function.

The FMR1 gene plays a key role in adult neurogenesis and neuroplasticity, and thus may contribute to age-related health in the population. The current study focused on the "low normal" FMR1 genotype, defined by lower-than-typical numbers of FMR1 CGG repeats (<26), as a potential genetic determinant of age-related health. We characterized the effect of the low normal FMR1 genotype on psychological well-being and motor function in a racially diverse non-clinical sample of older adult women. Women with low CGG repeats were distinguished from those with CGGs falling within the mid-high end of the normal range by reduced performance on multimodal assessments of motor function and psychological well-being, with large effect sizes. Robust continuous associations were also detected between lower CGG repeat length and reduced psychological well-being, balance, and dexterity. Findings suggest that FMR1 may represent an important mediator of individual differences in age-related health; larger epidemiological studies are needed. Given that approximately 23-35% of females carry the low normal genotype, efforts to understand its clinical effects have relevance a broad swath of the aging population.

Antidepressant Use Partially Mediates the Association Between Depression and Risk of Falls and Fall Injuries Among Older Adults.

BACKGROUND: The association between depression and fall risk in older adults is recognized, yet the mechanisms underlying this association are unclear. This study estimated the mediating role of antidepressant use in the association between depression and falls and fall injuries. METHODS: Longitudinal data from the Health and Retirement Study (2004-2006) were linked with medication data from the Prescription Drug Study (2005). The sample included community-dwelling adults aged ≥65 with data on depression and medication use (n = 3565). Depression was measured using 2 independent survey tools: Composite International Diagnostic Interview for depression short form and an 8-item version of the Center for Epidemiological Studies-Depression scale. We used causal mediation analysis to estimate and compare the direct and indirect (mediated by antidepressant use) effects of depression on falls and fall injuries. RESULTS: Individuals with major depressive disorder were significantly more likely to experience a fall (OR: 1.92; 95% CI: 1.41, 2.62) and a fall injury (OR: 1.67; 95% CI: 1.09, 2.55) over 2 years. Indirect effect estimates showed that antidepressant medication use accounted for approximately 19% and 18% of the association between major depressive disorder and falls and fall injuries, respectively. Results were similar when using an alternative depression measure and when considering only selective serotonin reuptake inhibitor antidepressants. CONCLUSIONS: Antidepressant use explains a significant proportion, but not a majority, of the association between depression and greater fall risk. Treatment benefits of antidepressants should be considered with, and may outweigh, concerns about increased risk of falls associated with antidepressant use.

Estimating causal effects in linear regression models with observational data: The instrumental variables regression model.

Instrumental variable methods are an underutilized tool to enhance causal inference in psychology. By way of incorporating predictors of the predictors (called "instruments" in the econometrics literature) into the model, instrumental variable regression (IVR) is able to draw causal inferences of a predictor on an outcome. We show that by regressing the outcome y on the predictors x and the predictors on the instruments, and modeling correlated disturbance terms between the predictor and outcome, causal inferences can be drawn on y on x if the IVR model cannot be rejected in a structural equation framework. We provide a tutorial on how to apply this model using ML estimation as implemented in structural equation modeling (SEM) software. We additionally provide code to identify instruments given a theoretical model, to select the best subset of instruments when more than necessary are available, and we guide researchers on how to apply this model using SEM. Finally, we demonstrate how the IVR model can be estimated using a number of estimators developed in econometrics (e.g., 2-stage least squares regression) and point out that the latter is simply a multistage SEM estimator of the IVR model. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Fitting Ordinal Factor Analysis Models With Missing Data: A Comparison Between Pairwise Deletion and Multiple Imputation.

This study compares two missing data procedures in the context of ordinal factor analysis models: pairwise deletion (PD; the default setting in Mplus) and multiple imputation (MI). We examine which procedure demonstrates parameter estimates and model fit indices closer to those of complete data. The performance of PD and MI are compared under a wide range of conditions, including number of response categories, sample size, percent of missingness, and degree of model misfit. Results indicate that both PD and MI yield parameter estimates similar to those from analysis of complete data under conditions where the data are missing completely at random (MCAR). When the data are missing at random (MAR), PD parameter estimates are shown to be severely biased across parameter combinations in the study. When the percentage of missingness is less than 50%, MI yields parameter estimates that are similar to results from complete data. However, the fit indices (i.e., χ2, RMSEA, and WRMR) yield estimates that suggested a worse fit than results observed in complete data. We recommend that applied researchers use MI when fitting ordinal factor models with missing data. We further recommend interpreting model fit based on the TLI and CFI incremental fit indices.

Pharmacokinetics and Pharmacodynamics of Immediate- and Modified-Release Mycophenolic Acid Preparations in Healthy Beagle Dogs.

Background: Mycophenolic acid (MPA) is a broad-acting immunomodulating agent that may be therapeutically beneficial for the treatment of immune-mediated diseases in canine patients. Objectives: To determine the suppressive effects of MPA on T-cell proliferation, and to assess the feasibility of a canine-specific q24 h modified-release MPA formulation (OKV-1001b). Animals: Fifteen healthy purpose-bred male beagle dogs. Methods: Two nearly identical open-label fifteen-day studies were conducted in which dogs were randomized to receive mycophenolate mofetil (MMF; 10 mg/kg q12h), or two doses of OKV-1001b (270 mg and 180 mg; q24h). Serial pharmacokinetic (PK) and pharmacodynamic (PD) samples were collected on Days 1, 8, and 15. MPA plasma concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), while an ex vivo T-cell proliferation assay assessed PD effects. Dogs were continuously monitored for evidence of side effects and gastrointestinal tolerability. Results: MPA induced inhibition of T-cell proliferation was observed following administration of all MPA preparations in a clear concentration-dependent manner. The PK/PD relationship was maintained across all days and time-points. Data generated herein suggest that MPA plasma concentrations above 600 ng/mL achieve at least 50% inhibition of T-cell proliferation. Conclusions and Clinical Importance: MPA holds therapeutic potential for treating dogs with immune-mediated disease, but clinical trials will be necessary to determine its safety and efficacy in naturally occurring disease. Likewise, q24h oral modified release MPA preparations that maintain MPA plasma concentrations between 600 and 1,000 ng/mL are warranted for further studies in client-owned dogs.

A general model for testing mediation and moderation effects.

This paper describes methods for testing mediation and moderation effects in a dataset, both together and separately. Investigations of this kind are especially valuable in prevention research to obtain information on the process by which a program achieves its effects and whether the program is effective for subgroups of individuals. A general model that simultaneously estimates mediation and moderation effects is presented, and the utility of combining the effects into a single model is described. Possible effects of interest in the model are explained, as are statistical methods to assess these effects. The methods are further illustrated in a hypothetical prevention program example.

Vagal Tone as a Putative Mechanism for Pragmatic Competence: An Investigation of Carriers of the FMR1 Premutation.

Pragmatic language skills exist across a continuum in typical and clinical populations, and are impaired in many neurodevelopmental disorders, most notably autism. The mechanisms underlying pragmatic impairment are poorly understood, although theory suggests dampened vagal tone plays a role. This study investigated the FMR1 premutation as a genetic model that may lend insight into the relationship between vagal function and pragmatic ability. Participants included 38 women with the FMR1 premutation and 23 controls. Vagal tone accounted for significant variance in pragmatics across both groups and statistically mediated the effect of FMR1 premutation status on pragmatic ability. Results support vagal tone as a biophysiological correlate of pragmatic ability, which informs potential mechanistic underpinnings and could have implications for targeted treatment.

An Empirical Mediation Analysis of Mechanisms Underlying HIV-1-Associated Neurocognitive Disorders.

HIV-1-associated neurocognitive disorders (HAND), characterized by alterations in the core components of cognitive function and age-related disease progression, persist in the post-cART era. However, the neurobehavioral mechanisms that mediate alterations in the core components of cognitive function and the progression of neurocognitive impairments have yet to be systematically evaluated. To address this knowledge gap, statistical mediation analysis was assessed, providing a critical opportunity to empirically evaluate putative neurobehavioral mechanisms underlying HAND. Neurocognitive assessments, conducted in HIV-1 transgenic (Tg) and control animals across the functional lifespan (i.e., Postnatal Day (PD) 30 to PD 600), tapped multiple cognitive domains including preattentive processes, learning, sustained attention, and long-term episodic memory. Three longitudinal mediation models were utilized to assess whether deficits in preattentive processes mediate alterations in learning, sustained attention and/or long-term episodic memory over time. Preattentive processes partially mediated the relationship between genotype and learning, genotype and sustained attention, and genotype and long-term episodic memory across the functional lifespan, explaining between 44% and 58% of the HIV-1 transgene effect. Understanding the neurobehavioral mechanisms mediating alterations in HAND may provide key targets for the development of a diagnostic biomarker, novel therapeutics, and cure/restoration strategies.