Exact distribution of a maximally selected Wilcoxon and a new hybrid test of symmetry
Laska, Eugene; Meisner, Morris; Wanderling, Joseph
Recently, a maximally selected normalized Wilcoxon, whose asymptotic distribution is a Brownian Bridge, was proposed for testing symmetry of a distribution about zero. The test sequentially discards observations whose absolute value is below increasing thresholds. The Wilcoxon is obtained at each threshold, and the maximum is the test statistic. We develop a recursive function for the exact distribution of a modification of the Max Wilcoxon test (MW) and provide critical values and a program for computing the p-value for a sample. A new hybrid test that combines the sign and MW tests is introduced. The power of MW and the new hybrid test are compared with Modarres and Gastwirth's hybrid test (MGH) and the Max McNemar (MM), under the generalized lambda distributions (GLD) family and two normal mixture models. The MW and the new hybrid test outperform the MGH, which is superior to the MM test in the GLD family. In one mixture model, MM is the least powerful test and the remaining three are essentially equivalent. In the second mixture model, when the zero median assumption is nearly valid, the MW test does well; its performance degrades when this assumption is violated. In the latter case, the MM performs better than MW for the same degree of skewness because the MM simultaneously tests both symmetry and zero median. Data from a genetic study of monozygotic twins discordant for major depressive disorder is used to illustrate the new tests
A maximally selected test of symmetry about zero
Laska, Eugene; Meisner, Morris; Wanderling, Joseph
The problem of testing symmetry about zero has a long and rich history in the statistical literature. We introduce a new test that sequentially discards observations whose absolute value is below increasing thresholds defined by the data. McNemar's statistic is obtained at each threshold and the largest is used as the test statistic. We obtain the exact distribution of this maximally selected McNemar and provide tables of critical values and a program for computing p-values. Power is compared with the t-test, the Wilcoxon Signed Rank Test and the Sign Test. The new test, MM, is slightly less powerful than the t-test and Wilcoxon Signed Rank Test for symmetric normal distributions with nonzero medians and substantially more powerful than all three tests for asymmetric mixtures of normal random variables with or without zero medians. The motivation for this test derives from the need to appraise the safety profile of new medications. If pre and post safety measures are obtained, then under the null hypothesis, the variables are exchangeable and the distribution of their difference is symmetric about a zero median. Large pre-post differences are the major concern of a safety assessment. The discarded small observations are not particularly relevant to safety and can reduce power to detect important asymmetry. The new test was utilized on data from an on-road driving study performed to determine if a hypnotic, a drug used to promote sleep, has next day residual effects
Prevalence of autism spectrum disorders in a total population sample
Kim, Young Shin; Leventhal, Bennett L; Koh, Yun-Joo; Fombonne, Eric; Laska, Eugene; Lim, Eun-Chung; Cheon, Keun-Ah; Kim, Soo-Jeong; Kim, Young-Key; Lee, Hyunkyung; Song, Dong-Ho; Grinker, Roy Richard
Objective: Experts disagree about the causes and significance of the recent increases in the prevalence of autism spectrum disorders (ASDs). Limited data on population base rates contribute to this uncertainty. Using a population-based sample, the authors sought to estimate the prevalence and describe the clinical characteristics of ASDs in school-age children. Method: The target population was all 7- to 12-year-old children (N=55,266) in a South Korean community; the study used a high-probability group from special education schools and a disability registry and a low-probability, general-population sample from regular schools. To identify cases, the authors used the Autism Spectrum Screening Questionnaire for systematic, multi-informant screening. Parents of children who screened positive were offered comprehensive assessments using standardized diagnostic procedures. Results: The prevalence of ASDs was estimated to be 2.64% (95% CI=1.91-3.37), with 1.89% (95% CI=1.43-2.36) in the general-population sample and 0.75% (95% CI=0.58-0.93) in the high-probability group. ASD characteristics differed between the two groups: the male-to-female ratios were 2.5:1 and 5.1:1 in the general population sample and high-probability group, respectively, and the ratios of autistic disorders to other ASD subtypes were 1:2.6 and 2.6:1, respectively; 12% in the general-population sample had superior IQs, compared with 7% in the high-probability group; and 16% in the general-population sample had intellectual disability, compared with 59% in the high-probability group. Conclusions: Two-thirds of ASD cases in the overall sample were in the mainstream school population, undiagnosed and untreated. These findings suggest that rigorous screening and comprehensive population coverage are necessary to produce more accurate ASD prevalence estimates and underscore the need for better detection, assessment, and services
Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder: A Randomized Clinical Trial
Bogenschutz, Michael P; Ross, Stephen; Bhatt, Snehal; Baron, Tara; Forcehimes, Alyssa A; Laska, Eugene; Mennenga, Sarah E; O'Donnell, Kelley; Owens, Lindsey T; Podrebarac, Samantha; Rotrosen, John; Tonigan, J Scott; Worth, Lindsay
Importance/UNASSIGNED:Although classic psychedelic medications have shown promise in the treatment of alcohol use disorder (AUD), the efficacy of psilocybin remains unknown. Objective/UNASSIGNED:To evaluate whether 2 administrations of high-dose psilocybin improve the percentage of heavy drinking days in patients with AUD undergoing psychotherapy relative to outcomes observed with active placebo medication and psychotherapy. Design, Setting, and Participants/UNASSIGNED:In this double-blind randomized clinical trial, participants were offered 12 weeks of manualized psychotherapy and were randomly assigned to receive psilocybin vs diphenhydramine during 2 day-long medication sessions at weeks 4 and 8. Outcomes were assessed over the 32-week double-blind period following the first dose of study medication. The study was conducted at 2 academic centers in the US. Participants were recruited from the community between March 12, 2014, and March 19, 2020. Adults aged 25 to 65 years with a DSM-IV diagnosis of alcohol dependence and at least 4 heavy drinking days during the 30 days prior to screening were included. Exclusion criteria included major psychiatric and drug use disorders, hallucinogen use, medical conditions that contraindicated the study medications, use of exclusionary medications, and current treatment for AUD. Interventions/UNASSIGNED:Study medications were psilocybin, 25 mg/70 kg, vs diphenhydramine, 50 mg (first session), and psilocybin, 25-40 mg/70 kg, vs diphenhydramine, 50-100 mg (second session). Psychotherapy included motivational enhancement therapy and cognitive behavioral therapy. Main Outcomes and Measures/UNASSIGNED:The primary outcome was percentage of heavy drinking days, assessed using a timeline followback interview, contrasted between groups over the 32-week period following the first administration of study medication using multivariate repeated-measures analysis of variance. Results/UNASSIGNED:A total of 95 participants (mean [SD] age, 46  years; 42 [44.2%] female) were randomized (49 to psilocybin and 46 to diphenhydramine). One participant (1.1%) was American Indian/Alaska Native, 5 (5.3%) were Black, 16 (16.8%) were Hispanic, and 75 (78.9%) were non-Hispanic White. Of the 95 randomized participants, 93 received at least 1 dose of study medication and were included in the primary outcome analysis. Percentage of heavy drinking days during the 32-week double-blind period was 9.7% for the psilocybin group and 23.6% for the diphenhydramine group, a mean difference of 13.9%; (95% CI, 3.0-24.7; F1,86â€‰=â€‰6.43; Pâ€‰=â€‰.01). Mean daily alcohol consumption (number of standard drinks per day) was also lower in the psilocybin group. There were no serious adverse events among participants who received psilocybin. Conclusions and Relevance/UNASSIGNED:Psilocybin administered in combination with psychotherapy produced robust decreases in percentage of heavy drinking days over and above those produced by active placebo and psychotherapy. These results provide support for further study of psilocybin-assisted treatment for AUD. Trial Registration/UNASSIGNED:ClinicalTrials.gov Identifier: NCT02061293.
A General Iterative Clustering Algorithm
Lin, Ziqiang; Laska, Eugene; Siegel, Carole
The quality of a cluster analysis of unlabeled units depends on the quality of the between units dissimilarity measures. Data dependent dissimilarity is more objective than data independent geometric measures such as Euclidean distance. As suggested by Breiman, many data driven approaches are based on decision tree ensembles, such as a random forest (RF), that produce a proximity matrix that can easily be transformed into a dissimilarity matrix. A RF can be obtained using labels that distinguish units with real data from units with synthetic data. The resulting dissimilarity matrix is input to a clustering program and units are assigned labels corresponding to cluster membership. We introduce a General Iterative Cluster (GIC) algorithm that improves the proximity matrix and clusters of the base RF. The cluster labels are used to grow a new RF yielding an updated proximity matrix which is entered into the clustering program. The process is repeated until convergence. The same procedure can be used with many base procedures such as the Extremely Randomized Tree ensemble. We evaluate the performance of the GIC algorithm using benchmark and simulated data sets. The properties measured by the Silhouette Score are substantially superior to the base clustering algorithm. The GIC package has been released in R: https://cran.r-project.org/web/packages/GIC/index.html.
A likely responder approach for the analysis of randomized controlled trials
Laska, Eugene; Siegel, Carole; Lin, Ziqiang
OBJECTIVE:To further the precision medicine goal of tailoring medical treatment to individual patient characteristics by providing a method of analysis of the effect of test treatment, T, compared to a reference treatment, R, in participants in a RCT who are likely responders to T. METHODS:Likely responders to T are individuals whose expected response at baseline exceeds a prespecified minimum. A prognostic score, the expected response predicted as a function of baseline covariates, is obtained at trial completion. It is a balancing score that can be used to match likely responders randomized to T with those randomized to R; the result is comparable treatment groups that have a common covariance distribution. Treatments are compared based on observed outcomes in this enriched sample. The approach is illustrated in a RCT comparing two treatments for opioid use disorder. RESULTS:A standard statistical analysis of the opioid use disorder RCT found no treatment difference in the total sample. However, a subset of likely responders to T were identified and in this group, T was statistically superior to R. CONCLUSION/CONCLUSIONS:The causal treatment effect of T relative to R among likely responders may be more important than the effect in the whole target population. The prognostic score function provides quantitative information to support patient specific treatment decisions regarding T furthering the goal of precision medicine.
Identifying subtypes of PTSD to promote precision medicine
Siegel, Carole; Laska, Eugene
Pre-deployment risk factors for PTSD in active-duty personnelÂ deployed to Afghanistan: a machine-learning approach for analyzing multivariate predictors
Schultebraucks, Katharina; Qian, Meng; Abu-Amara, Duna; Dean, Kelsey; Laska, Eugene; Siegel, Carole; Gautam, Aarti; Guffanti, Guia; Hammamieh, Rasha; Misganaw, Burook; Mellon, Synthia H; Wolkowitz, Owen M; Blessing, Esther M; Etkin, Amit; Ressler, Kerry J; Doyle, Francis J; Jett, Marti; Marmar, Charles R
Active-duty Army personnel can be exposed to traumatic warzone events and are at increased risk for developing post-traumatic stress disorder (PTSD) compared with the general population. PTSD is associated with high individual and societal costs, but identification of predictive markers to determine deployment readiness and risk mitigation strategies is not well understood. This prospective longitudinal naturalistic cohort study-the Fort Campbell Cohort study-examined the value of using a large multidimensional dataset collected from soldiers prior to deployment to Afghanistan for predicting post-deployment PTSD status. The dataset consisted of polygenic, epigenetic, metabolomic, endocrine, inflammatory and routine clinical lab markers, computerized neurocognitive testing, and symptom self-reports. The analysis was computed on active-duty Army personnel (Nâ€‰=â€‰473) of the 101st Airborne at Fort Campbell, Kentucky. Machine-learning models predicted provisional PTSD diagnosis 90-180 days post deployment (random forest: AUCâ€‰=â€‰0.78, 95% CIâ€‰=â€‰0.67-0.89, sensitivityâ€‰=â€‰0.78, specificityâ€‰=â€‰0.71; SVM: AUCâ€‰=â€‰0.88, 95% CIâ€‰=â€‰0.78-0.98, sensitivityâ€‰=â€‰0.89, specificityâ€‰=â€‰0.79) and longitudinal PTSD symptom trajectories identified with latent growth mixture modeling (random forest: AUCâ€‰=â€‰0.85, 95% CIâ€‰=â€‰0.75-0.96, sensitivityâ€‰=â€‰0.88, specificityâ€‰=â€‰0.69; SVM: AUCâ€‰=â€‰0.87, 95% CIâ€‰=â€‰0.79-0.96, sensitivityâ€‰=â€‰0.80, specificityâ€‰=â€‰0.85). Among the highest-ranked predictive features were pre-deployment sleep quality, anxiety, depression, sustained attention, and cognitive flexibility. Blood-based biomarkers including metabolites, epigenomic, immune, inflammatory, and liver function markers complemented the most important predictors. The clinical prediction of post-deployment symptom trajectories and provisional PTSD diagnosis based on pre-deployment data achieved high discriminatory power. The predictive models may be used to determine deployment readiness and to determine novel pre-deployment interventions to mitigate the risk for deployment-related PTSD.
Utilization of machine learning for identifying symptom severity military-related PTSD subtypes and their biological correlates
Siegel, Carole E; Laska, Eugene M; Lin, Ziqiang; Xu, Mu; Abu-Amara, Duna; Jeffers, Michelle K; Qian, Meng; Milton, Nicholas; Flory, Janine D; Hammamieh, Rasha; Daigle, Bernie J; Gautam, Aarti; Dean, Kelsey R; Reus, Victor I; Wolkowitz, Owen M; Mellon, Synthia H; Ressler, Kerry J; Yehuda, Rachel; Wang, Kai; Hood, Leroy; Doyle, Francis J; Jett, Marti; Marmar, Charles R
We sought to find clinical subtypes of posttraumatic stress disorder (PTSD) in veterans 6-10 years post-trauma exposure based on current symptom assessments and to examine whether blood biomarkers could differentiate them. Samples were males deployed to Iraq and Afghanistan studied by the PTSD Systems Biology Consortium: a discovery sample of 74 PTSD cases and 71 healthy controls (HC), and a validation sample of 26 PTSD cases and 36 HC. A machine learning method, random forests (RF), in conjunction with a clustering method, partitioning around medoids, were used to identify subtypes derived from 16 self-report and clinician assessment scales, including the clinician-administered PTSD scale for DSM-IV (CAPS). Two subtypes were identified, designated S1 and S2, differing on mean current CAPS total scores: S2â€‰=â€‰75.6 (sd 14.6) and S1â€‰=â€‰54.3 (sd 6.6). S2 had greater symptom severity scores than both S1 and HC on all scale items. The mean first principal component score derived from clinical summary scales was three times higher in S2 than in S1. Distinct RFs were grown to classify S1 and S2 vs. HCs and vs. each other on multi-omic blood markers feature classes of current medical comorbidities, neurocognitive functioning, demographics, pre-military trauma, and psychiatric history. Among these classes, in each RF intergroup comparison of S1, S2, and HC, multi-omic biomarkers yielded the highest AUC-ROCs (0.819-0.922); other classes added little to further discrimination of the subtypes. Among the top five biomarkers in each of these RFs were methylation, micro RNA, and lactate markers, suggesting their biological role in symptom severity.
CRF serum levels differentiate PTSD from healthy controls and TBI in military veterans
Ramos-Cejudo, Jaime; Genfi, Afia; Abu-Amara, Duna; Debure, Ludovic; Qian, Meng; Laska, Eugene; Siegel, Carole; Milton, Nicholas; Newman, Jennifer; Blessing, Esther; Li, Meng; Etkin, Amit; Marmar, Charles R; Fossati, Silvia
Background and Objective/UNASSIGNED:Posttraumatic stress disorder (PTSD) is a serious and frequently debilitating psychiatric condition that can occur in people who have experienced traumatic stessors, such as war, violence, sexual assault and other life-threatening events. Treatment of PTSD and traumatic brain injury (TBI) in veterans is challenged by diagnostic complexity, partially due to PTSD and TBI symptom overlap and to the fact that subjective self-report assessments may be influenced by a patient's willingness to share their traumatic experiences and resulting symptoms. Corticotropin-releasing factor (CRF) is one of the main mediators of hypothalamic pituitary adrenal (HPA)-axis responses in stress and anxiety. Methods and Results/UNASSIGNED:We analyzed serum CRF levels in 230 participants including heathy controls (64), and individuals with PTSD (53), TBI (70) or PTSD+TBI (43) by enzyme immunoassay (EIA). Significantly lower CRF levels were found in both the PTSD and PTSD+TBI groups compared to healthy control (PTSD vs Controls: P=0.0014, PTSD + TBI vs Controls: P=0.0011) and chronic TBI participants (PTSD vs TBI: P<0.0001PTSD + TBI vs TBI: P<0.0001) , suggesting a PTSD-related mechanism independent from TBI and associated with CRF reduction. CRF levels negatively correlated with PTSD severity on the CAPS-5 scale in the whole study group. Conclusions/UNASSIGNED:Hyperactivation of the HPA axis has been classically identified in acute stress. However, the recognized enhanced feedback inhibition of the HPA axis in chronic stress supports our findings of lower CRF in PTSD patients. This study suggests that reduced serum CRF in PTSD should be further investigated. Future validation studies will establish if CRF is a possible blood biomarker for PTSD and/or for differentiating PTSD and chronic TBI symptomatology.