A novel biomarker selection method using multimodal neuroimaging data.

Identifying biomarkers is essential to obtain the optimal therapeutic benefit while treating patients with late-life depression (LLD). We compare LLD patients with healthy controls (HC) using resting-state functional magnetic resonance and diffusion tensor imaging data to identify neuroimaging biomarkers that may be potentially associated with the underlying pathophysiology of LLD. We implement a Bayesian multimodal local false discovery rate approach for functional connectivity, borrowing strength from structural connectivity to identify disrupted functional connectivity of LLD compared to HC. In the Bayesian framework, we develop an algorithm to control the overall false discovery rate of our findings. We compare our findings with the literature and show that our approach can better detect some regions never discovered before for LLD patients. The Hub of our discovery related to various neurobehavioral disorders can be used to develop behavioral interventions to treat LLD patients who do not respond to antidepressants.

Development of a Bayesian multimodal model to detect biomarkers in neuroimaging studies.

In this article, we developed a Bayesian multimodal model to detect biomarkers (or neuromarkers) using resting-state functional and structural data while comparing a late-life depression group with a healthy control group. Biomarker detection helps determine a target for treatment intervention to get the optimal therapeutic benefit for treatment-resistant patients. The borrowing strength of the structural connectivity has been quantified for functional activity while detecting the biomarker. In the biomarker searching process, thousands of hypotheses are generated and tested simultaneously using our novel method to control the false discovery rate for small samples. Several existing statistical approaches, frequently used in analyzing neuroimaging data have been investigated and compared via simulation with the proposed approach to show its excellent performance. Results are illustrated with a live data set generated in a late-life depression study. The role of detected biomarkers in terms of cognitive function has been explored.

Detection of sparse differential dependent functional brain connectivity.

Functional brain connectivity analysis is an increasingly important technique in neuroscience, psychiatry, and autism research. Functional connectivity can be measured by considering co-activation of brain regions in resting-state functional magnetic resonance imaging (rs-fMRI). We propose a novel Bayesian model to detect differential connections in cross-correlated functional connectivity between region of interest (ROI) pairs. The proposed sparse clustered neighborhood model induces a lower-dimensional sparsity and clustering based on a nonparametric Bayesian approach to model sparse differentially connected ROI pairs. Second, it induces a structured dependence model for modeling potential dependence among ROI pairs. We demonstrate Bayesian inference and performance of the proposed model in simulation studies and compare with a standard model. We utilize the proposed model to contrast functional connectivities between participants with autism spectrum disorder and neurotypical participants using cross-correlated rs-fMRI data from four sites of the Autism Brain Image Data Exchange.

An Initial miRNA Profile of Persons With Persisting Neurobehavioral Impairments and States of Disordered Consciousness After Severe Traumatic Brain Injury.

OBJECTIVE: To examine the merits of using microRNAs (miRNAs) as biomarkers of disorders of consciousness (DoC) due to traumatic brain injury (TBI). SETTINGS: Acute and subacute beds. PARTICIPANTS: Patients remaining in vegetative and minimally conscious states (VS, MCS), an average of 1.5 years after TBI, and enrolled in a randomized clinical trial ( n = 6). Persons without a diagnosed central nervous system disorder, neurotypical controls ( n = 5). DESIGN: Comparison of whole blood miRNA profiles between patients and age/gender-matched controls. For patients, correlational analyses between miRNA profiles and measures of neurobehavioral function. MAIN MEASURES: Baseline measures of whole blood miRNAs isolated from the cellular and fluid components of blood and measured using miRNA-seq and real-time polymerase chain reaction (RT-PCR). Baseline neurobehavioral measures derived from 7 tests. RESULTS: For patients, relative to controls, 48 miRNA were significantly ( P < .05)/differentially expressed. Cluster analysis showed that neurotypical controls were most similar to each other and with 2 patients (VS: n = 1; and MCS: n = 1). Three patients, all in MCS, clustered separately. The only female in the sample, also in MCS, formed an independent group. For the 48 miRNAs, the enriched pathways identified are implicated in secondary brain damage and 26 miRNAs were significantly ( P < .05) correlated with measures of neurobehavioral function. CONCLUSIONS: Patients remaining in states of DoC an average of 1.5 years after TBI showed a different and reproducible pattern of miRNA expression relative to age/gender-matched neurotypical controls. The phenotypes, defined by miRNA profiles relative to persisting neurobehavioral impairments, provide the basis for future research to determine the miRNA profiles differentiating states of DoC and the basis for future research using miRNA to detect treatment effects, predict treatment responsiveness, and developing targeted interventions. If future research confirms and advances reported findings, then miRNA profiles will provide the foundation for patient-centric DoC neurorehabilitation.

Longitudinal Changes in the Composition of the Penile Microbiome Are Associated With Circumcision Status, HIV and HSV-2 Status, Sexual Practices, and Female Partner Microbiome Composition.

Background: Penile microbiome composition has been associated with HSV-2 and HIV in men and with bacterial vaginosis (BV) and HSV-2 in female sex partners. This study sought to 1) characterize penile microbiome composition over a 1-year period and 2) identify factors associated with penile microbiome composition over time. Methods: This prospective study of community-recruited heterosexual couples in Kenya measured penile and vaginal microbiomes via 16S ribosomal RNA gene amplicon sequencing at 4 time points over 1 year (1, 6, and 12 months after baseline). We used longitudinal mixed-effects modeling to assess associated demographic, behavioral, and disease factors and changes in community type, meatal taxa with the highest mean relative abundance, and alpha and beta diversity measures. We estimated group-based trajectories to elucidate compositional trends. Results: Among 218 men with 740 observations, men had a median age of 26 years, 11.6% were living with HIV, and 46.1% were HSV-2 seropositive. We identified 7 penile community types that varied with circumcision status, female partner vaginal microbiome community state type (CST), condom use, and penile washing. Across varying analytic approaches, 50%-60% of men had stable penile microbiome compositions. Alpha diversity measures were lower for circumcised men and those who reported condom use; they were stable over time but higher if female partners had diverse CSTs or BV. BV was positively associated with the relative abundance of numerous individual penile taxa. The decreased Bray-Curtis similarity was more common for men with HSV-2, and HSV-2 was also associated with a lower relative abundance of Corynebacterium and Staphylococcus. Conclusions: Over a 1-year period, penile microbiome composition was stable for a substantial proportion of men and was influenced by men's circumcision status, sexual practices, female partner's vaginal CST and BV status, and men's HSV-2 status. In the female genital tract, a diverse CST is often associated with poorer health outcomes. Our results contribute toward understanding whether this framework extends to the penile microbiome and whether diversity and the associated penile microbiome compositions influence susceptibility or resilience to poorer health outcomes in men. Focusing on understanding how these factors influence the penile microbiome may lead to therapeutic avenues for reduced HSV-2 and BV infections in men and their female sex partners.

Feasibility of a Combined Neuromodulation and Yoga Intervention for Mild Traumatic Brain Injury and Chronic Pain: Protocol for an Open-label Pilot Trial.

BACKGROUND: Mild traumatic brain injury (mTBI) and chronic pain often co-occur and worsen rehabilitation outcomes. There is a need for improved multimodal nonpharmacologic treatments that could improve outcomes for both conditions. Yoga is a promising activity-based intervention for mTBI and chronic pain, and neuromodulation through transcranial magnetic stimulation is a promising noninvasive, nonpharmacological treatment for mTBI and chronic pain. Intermittent theta burst stimulation (iTBS) is a type of patterned, excitatory transcranial magnetic stimulation. iTBS can induce a window of neuroplasticity, making it ideally suited to boost the effects of treatments provided after it. Thus, iTBS may magnify the impacts of subsequently delivered interventions as compared to delivering those interventions alone and accordingly boost their impact on outcomes. OBJECTIVE: The aim of this study is to (1) develop a combined iTBS+yoga intervention for mTBI and chronic pain, (2) assess the intervention's feasibility and acceptability, and (3) gather preliminary clinical outcome data on quality of life, function, and pain that will guide future studies. METHODS: This is a mixed methods, pilot, open-labeled, within-subject intervention study. We will enroll 20 US military veteran participants. The combined iTBS+yoga intervention will be provided in small group settings once a week for 6 weeks. The yoga intervention will follow the LoveYourBrain yoga protocol-specifically developed for individuals with TBI. iTBS will be administered immediately prior to the LoveYourBrain yoga session. We will collect preliminary quantitative outcome data before and after the intervention related to quality of life (TBI-quality of life), function (Mayo-Portland Adaptability Index), and pain (Brief Pain Inventory) to inform larger studies. We will collect qualitative data via semistructured interviews focused on intervention acceptability after completion of the intervention. RESULTS: This study protocol was approved by Edward Hines Jr Veterans Administration Hospital Institutional Review Board (Hines IRB 1573116-4) and was prospectively registered on ClinicalTrials.gov (NCT04517604). This study includes a Food and Drug Administration Investigational Device Exemption (IDE: G200195). A 2-year research plan timeline was developed. As of March 2022, a total of 6 veterans have enrolled in the study. Data collection is ongoing and will be completed by November 2022. We expect the results of this study to be available by October 2024. CONCLUSIONS: We will be able to provide preliminary evidence of safety, feasibility, and acceptability of a novel combined iTBS and yoga intervention for mTBI and chronic pain-conditions with unmet treatment needs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04517604; https://www.clinicaltrials.gov/ct2/show/NCT04517604. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/37836.

Vaginal and Penile Microbiome Associations With Herpes Simplex Virus Type 2 in Women and Their Male Sex Partners.

BACKGROUND: We determined how the vaginal and penile microbiomes contribute to herpes simplex virus type 2 (HSV-2) serostatus within sexual partnerships. METHODS: Microbiomes were characterized in cervicovaginal lavage and penile meatal swab specimens through high-throughput 16s ribosomal RNA gene amplicon sequencing. HSV-2 antibody was detected in serum specimens. We modeled vaginal and penile taxa and covariates contributing to HSV-2 status in women and men using bivariate probit analysis. RESULTS: Among 231 couples, HSV-2 was detected in both partners in 78 couples (33.8%), in the woman only in 52 (22.5%),in the man only in 27 (11.7%), and in neither in 74 (32.0%). Among the women (median age, 22 years) 10.9% had human immunodeficiency virus (HIV), and 21.4% had Bacterial vaginosis. Among men (median age, 26 years), 11.8% had HIV, and 55.0% circumcised. In an analysis with adjustment for sociodemographics and Bacterial vaginosis, enrichment of vaginal Gardnerella vaginalis and Lactobacillus iners was associated with increased likelihood of HSV-2 in both partners. Penile taxa (including Ureaplasma and Aerococcus) were associated with HSV-2 in women. CONCLUSIONS: We demonstrate that penile taxa are associated with HSV-2 in female partners, and vaginal taxa are associated with HSV-2 in male partners. Our findings suggest that couples-level joint consideration of genital microbiome and sexually transmitted infection or related outcomes could lead to new avenues for prevention.

Generalized confidence interval for an agreement between raters.

Estimation and inference are two key components toward the solution of any statistical problem; however, the inferential issues of statistical assessment of agreement among two or more raters have not been well developed as compared to the development of estimation procedures in this area. The fundamental reason for this gap is the complex expression of the concordance correlation coefficient (CCC) that is frequently used in assessing agreement among raters. Large sample-based statistical tests for CCC often fail to produce desired results for small samples. Hence, inferential procedures for small samples are urgently needed to evaluate agreement between raters. We argue that hypothesis testing of CCC has little value in practice due to the absence of a gold standard of agreement. In this article, we construct the generalized confidence interval (GCI) for CCC utilizing a bivariate normal distribution of measurements, and also develop a large sample-based confidence interval (LSCI). We establish satisfactory performance of GCI by providing the desired coverage probability (CP) via simulation. Results of GCI and LSCI are illustrated and compared with a data set of a recent study performed at U.S. Department of Veterans Affairs, Hines.

Schistosomiasis is associated with rectal mucosal inflammation among Kenyan men who have sex with men.

Background:Schistosoma mansoni infection is hyperendemic in Lake Victoria communities and associated with cervicovaginal immune alterations and HIV acquisition. We assessed the hypothesis that schistosomiasis correlates with greater rectal inflammation in men who have sex with men (MSM) in Kisumu, Kenya. Methods: In this cross-sectional study of 38 HIV-negative MSM aged 18-35 years, schistosomiasis was diagnosed by urine circulating cathodic antigen (CCA). Microbiome was assessed in rectal swabs by 16S rRNA gene amplicon sequencing, and rectal inflammation by quartile normalized summative score of inflammatory cytokines (IL-1α, IL-1ß, IL-8, and TNF-α). Elastic net (EN) regression identified taxa associated with inflammation. Multivariable linear regression estimated the association between inflammation score and schistosomiasis and bacteria identified in EN. Results: Most men were CCA positive (24/38; 63%), and median rectal inflammation score was significantly higher in these participants (11 vs. 8, p = 0.04). In multivariable regression, CCA-positive men had 2.85-point greater inflammation score (p = 0.009). The relative abundance of Succinivibrio (coefficient = -1.13, p = 0.002) and Pseudomonas (coefficient = -1.04, p = 0.001) were negatively associated with inflammation. Discussion: CCA positivity was associated with rectal mucosal inflammation, controlling for rectal microbiome composition. Given its high prevalence and contribution to inflammation, schistosomiasis may have important implications for HIV transmission in this vulnerable population.

After-School Programs and Children's Mental Health: Organizational Social Context, Program Quality, and Children's Social Behavior.

OBJECTIVE: The current study examined associations among organizational social context, after-school program (ASP) quality, and children's social behavior in a large urban park district. METHOD: Thirty-two park-based ASPs are included in the final sample, including 141 staff and 593 children. Staff reported on organizational culture (rigidity, proficiency, resistance) and climate (engagement, functionality, stress), and children's social skills and problem behaviors. Children and their parents reported on program quality indicators (e.g., activities, routines, relationships). Parents also completed a children's mental health screener. RESULTS: A series of Hierarchical Linear Models revealed that proficiency and stress were the only organizational predictors of program quality; associations between stress and program quality were moderated by program enrollment and aggregated children's mental health need. Higher child- and parent-perceived program quality related to fewer staff-reported problem behaviors, while overall higher enrollment and higher aggregated mental health need were associated with fewer staff-reported social skills. CONCLUSIONS: Data are informing ongoing efforts to improve organizational capacity of urban after-school programs to support children's positive social and behavior trajectories.

miRNAs as Potential Biomarkers for Traumatic Brain Injury: Pathway From Diagnosis to Neurorehabilitation.

BACKGROUND: Biomarkers that can advance precision neurorehabilitation of the traumatic brain injury (TBI) are needed. MicroRNAs (miRNAs) have biological properties that could make them well suited for playing key roles in differential diagnoses and prognoses and informing likelihood of responsiveness to specific treatments. OBJECTIVE: To review the evidence of miRNA alterations after TBI and evaluate the state of science relative to potential neurorehabilitation applications of TBI-specific miRNAs. METHODS: This scoping review includes 57 animal and human studies evaluating miRNAs after TBI. PubMed, Scopus, and Google Scholar search engines were used. RESULTS: Gold standard analytic steps for miRNA biomarker assessment are presented. Published studies evaluating the evidence for miRNAs as potential biomarkers for TBI diagnosis, severity, natural recovery, and treatment-induced outcomes were reviewed including statistical evaluation. Growing evidence for specific miRNAs, including miR21, as TBI biomarkers is presented. CONCLUSIONS: There is evidence of differential miRNA expression in TBI in both human and animal models; however, gaps need to be filled in terms of replication using rigorous, standardized methods to isolate a consistent set of miRNA changes. Longitudinal studies in TBI are needed to understand how miRNAs could be implemented as biomarkers in clinical practice.

Neural Connectivity Changes Facilitated by Familiar Auditory Sensory Training in Disordered Consciousness: A TBI Pilot Study.

For people with disordered consciousness (DoC) after traumatic brain injury (TBI), relationships between treatment-induced changes in neural connectivity and neurobehavioral recovery have not been explored. To begin building a body of evidence regarding the unique contributions of treatments to changes in neural network connectivity relative to neurobehavioral recovery, we conducted a pilot study to identify relationships meriting additional examination in future research. To address this objective, we examined previously unpublished neural connectivity data derived from a randomized clinical trial (RCT). We leveraged these data because treatment efficacy, in the RCT, was based on a comparison of a placebo control with a specific intervention, the familiar auditory sensory training (FAST) intervention, consisting of autobiographical auditory-linguistic stimuli. We selected a subgroup of RCT participants with high-quality imaging data (FAST n = 4 and placebo n = 4) to examine treatment-related changes in brain network connectivity and how and if these changes relate to neurobehavioral recovery. To discover promising relationships among the FAST intervention, changes in neural connectivity, and neurobehavioral recovery, we examined 26 brain regions and 19 white matter tracts associated with default mode, salience, attention, and language networks, as well as three neurobehavioral measures. Of the relationships discovered, the systematic filtering process yielded evidence supporting further investigation of the relationship among the FAST intervention, connectivity of the left inferior longitudinal fasciculus, and auditory-language skills. Evidence also suggests that future mechanistic research should focus on examining the possibility that the FAST supports connectivity changes by facilitating redistribution of brain resources. For a patient population with limited treatment options, the reported findings suggest that a simple, yet targeted, passive sensory stimulation treatment may have altered functional and structural connectivity. If replicated in future research, then these findings provide the foundation for characterizing the unique contributions of the FAST intervention and could inform development of new treatment strategies. For persons with severely damaged brain networks, this report represents a first step toward advancing understanding of the unique contributions of treatments to changing brain network connectivity and how these changes relate to neurobehavioral recovery for persons with DoC after TBI. Clinical Trial Registry: NCT00557076, The Efficacy of Familiar Voice Stimulation During Coma Recovery (http://www.clinicaltrials.gov).

A Pilot Trial Examining the Merits of Combining Amantadine and Repetitive Transcranial Magnetic Stimulation as an Intervention for Persons With Disordered Consciousness After TBI.

OBJECTIVE: Report pilot findings of neurobehavioral gains and network changes observed in persons with disordered consciousness (DoC) who received repetitive transcranial magnetic stimulation (rTMS) or amantadine (AMA), and then rTMS+AMA. PARTICIPANTS: Four persons with DoC 1 to 15 years after traumatic brain injury (TBI). DESIGN: Alternate treatment-order, within-subject, baseline-controlled trial. MAIN MEASURES: For group and individual neurobehavioral analyses, predetermined thresholds, based on mixed linear-effects models and conditional minimally detectable change, were used to define meaningful neurobehavioral change for the Disorders of Consciousness Scale-25 (DOCS) total and Auditory-Language measures. Resting-state functional connectivity (rsFC) of the default mode and 6 other networks was examined. RESULTS: Meaningful gains in DOCS total measures were observed for 75% of treatment segments and auditory-language gains were observed after rTMS, which doubled when rTMS preceded rTMS+AMA. Neurobehavioral changes were reflected in rsFC for language, salience, and sensorimotor networks. Between networks interactions were modulated, globally, after all treatments. CONCLUSIONS: For persons with DoC 1 to 15 years after TBI, meaningful neurobehavioral gains were observed after provision of rTMS, AMA, and rTMS+AMA. Sequencing and combining of treatments to modulate broad-scale neural activity, via differing mechanisms, merits investigation in a future study powered to determine efficacy of this approach to enabling neurobehavioral recovery.

The Microbiome Composition of a Man's Penis Predicts Incident Bacterial Vaginosis in His Female Sex Partner With High Accuracy.

Background: We determined the predictive accuracy of penile bacteria for incident BV in female sex partners. In this prospective cohort, we enrolled Kenyan men aged 18-35 and their female sex partners aged 16 and older. We assessed BV at baseline, 1, 6, and 12 months. Incident BV was defined as a Nugent score of 7-10 at a follow-up visit, following a Nugent score of 0-6 at baseline. Amplification of the V3-V4 region of the bacterial 16S rRNA gene was performed on meatal and glans/coronal sulcus swab samples. Majority vote classifier combined the decisions of three machine learning classification algorithms (Random Forest, Support Vector Machine, K Nearest Neighbor). We report the estimate cross-validation predictive accuracy for incident BV based on baseline penile taxa. Results: The incidence of BV was 31% among 168 couples in which the woman did not have BV at baseline: 37.3% if the man was uncircumcised vs. 26.3% if the man was circumcised. Incident BV occurred at 1 month (n = 23), 6 months (n = 20), 12 months (n = 9). The predictive capacity of meatal taxa was high: sensitivity (80.7%), specificity (74.6%), accuracy (77.5%), area under the curve (88.8%). Variable importance ranking identified meatal taxa that in the vagina are associated with BV: Parvimonas, Lactobacillus iners, L. crispatus, Dialister, Sneathia sanguinegens, and Gardnerella vaginalis were among the top 10 most predictive taxa. The accuracy of glans/coronal sulcus taxa to predict incident BV was comparable to meatal taxa accuracy, but with greater variability. Conclusions: Baseline penile microbiota accurately predicted BV incidence in women who did not have BV at baseline, with more than half of incident infections observed at 6- to 12- months after penile microbiome assessment. These results suggest interventions to manipulate the penile microbiome may reduce BV incidence in sex partners, and that potential treatment (antibiotic or live biotherapeutic) will need to be effective in reducing or altering bacteria at both the glans/coronal sulcus and urethral sites (as represented by the meatus). The temporal association clarifies that concordance of penile microbiome with the vaginal microbiome of sex partners is not merely reflecting the vaginal microbiome, but can contribute to it.

Characteristics of Women and Their Male Sex Partners Predict Bacterial Vaginosis Among a Prospective Cohort of Kenyan Women With Nonoptimal Vaginal Microbiota.

BACKGROUND: Up to 50% of women with nonoptimal vaginal microbial community state type (CST) have bacterial vaginosis (BV). Little is known about what distinguishes women with and without BV diagnosis within nonoptimal CST. We identified features of women and their male sex partners associated with BV among women with nonoptimal vaginal CST. METHODS: In this prospective study, 252 heterosexual couples were observed at 1, 6, and 12 months after baseline. Microbiomes were characterized in cervicovaginal lavage and penile meatal swabs through high-throughput 16s ribosomal RNA gene amplicon sequencing. Nonoptimal CST was defined as CST-IV. Bacterial vaginosis was defined as a Nugent score of 7 to 10. Generalized estimating equation analysis estimated adjusted odds ratios (aORs) for BV among women with nonoptimal CST. RESULTS: At baseline, women with nonoptimal CST were a median age of 22 years, 44% had BV, 16% had HIV, and 66% had herpes simplex virus (HSV) type 2. Male partners were a median age of 27 years, 12% had HIV, 48% had HSV-2, and 55% were circumcised. Within nonoptimal CST, Sneathia sanguinegens, Prevotella species, Prevotella amnii, and Clostridiales, BV-associated bacteria-2 were statistically significantly enriched in observations with BV. In multivariable generalized estimating equation controlling for CST, HIV, and HSV-2, BV was increased among women with CST-IVA (aOR, 1.91; P = 0.087), HIV (aOR, 2.30; P = 0.051), HSV-2 (aOR, 1.75; P = 0.065), and enrichment of male partner penile taxa: Dialister (aOR, 1.16; P = 0.034), Megasphaera (aOR, 1.22; P = 0.001), and Brevibacterium (aOR, 1.13; P = 0.019).These results provide insights into factors differentiating women with BV among those with nonoptimal vaginal CST. Interrupting the sexual exchange of penile and vaginal taxa may be beneficial for preventing pathologic state of vaginal microbiome.

Quantification of intrinsic subtype ambiguity in Luminal A breast cancer and its relationship to clinical outcomes.

BACKGROUND: PAM50 gene profiling assigns each cancer to a single intrinsic subtype. However, individual cancers vary in their adherence to a prototype, and due to bulk tissue sampling, some may exhibit expression patterns that indicate intra-tumor admixture of multiple subtypes. Our objective was to develop admixture metrics from PAM50 gene expression profiles in order to stratify Luminal A (LumA) cases according to their degree of subtype admixture, and then relate such admixture to clinical and molecular variables. METHODS: We re-constructed scaled, normalized PAM50 profiles for 1980 cases (674 LumA) in the METABRIC cohort and for each case computed its Mahalanobis (M-) distance from its assigned centroid and M-distance from all other centroids. We used t-SNE plots to visualize overlaps in subtype clustering. With Normal-like cases excluded, we developed two metrics: Median Distance Criteria (MDC) classified pure cases as those located within the 50th percentile of the LumA centroid and > =50th percentile from any other centroid. Distance Ratio Criteria (DRC) was computed as the ratio of M-distances from the LumA centroid to the nearest non-assigned centroid. Pure and admixed LumA cases were compared on clinical/molecular traits. TCGA LumA cases (n = 509) provided independent validation. RESULTS: Compared to pure cases in METABRIC, admixed ones had older age at diagnosis, larger tumor size, and higher grade and stage. These associations were stronger for the DRC metric compared to MDC. Admixed cases were associated with HER2 gain, high proliferation, higher PAM50 recurrence scores, more frequent TP53 mutation, and less frequent PIK3CA mutation. Similar results were observed in the TCGA validation cohort, which also showed a positive association between admixture and number of clonal populations estimated by PyClone. LumA-LumB confusion predominated, but other combinations were also present. Degree of admixture was associated with overall survival in both cohorts, as was disease-free survival in TCGA, independent of age, grade and stage (HR = 2.85, Tertile 3 vs.1). CONCLUSIONS: Luminal A breast cancers subgrouped based on PAM50 subtype purity support the hypothesis that admixed cases have worse clinical features and survival. Future analyses will explore more extensive genomic metrics for admixture and their spatial significance within a single tumor.

Mental Health Self-Directed Care Financing: Efficacy in Improving Outcomes and Controlling Costs for Adults With Serious Mental Illness.

OBJECTIVE: Self-directed care allows individuals with disabilities and elderly persons to control public funds to purchase goods and services that help them remain outside institutional settings. This study examined effects on outcomes, service costs, and user satisfaction among adults with serious mental illness. METHODS: Public mental health system clients were randomly assigned to self-directed care (N=114) versus services as usual (N=102) and assessed at baseline and 12 and 24 months. The primary outcome was self-perceived recovery. Secondary outcomes included psychosocial status, psychiatric symptom severity, and behavioral rehabilitation indicators. Mixed-effects random-regression analysis tested for longitudinal changes in outcomes between the two conditions. Differences in service costs were analyzed with negative binomial and zero-inflated negative binomial regression models. RESULTS: Compared with the control group, self-directed care participants had significantly greater improvement over time in recovery, self-esteem, coping mastery, autonomy support, somatic symptoms, employment, and education. No between-group differences were found in total per-person service costs in years 1 and 2 or both years combined. However, self-directed care participants were more likely than control group participants to have zero costs for six of 12 individual services and to have lower costs for four. The most frequent nontraditional purchases were for transportation (21%), communication (17%), medical care (15%), residential (14%), and health and wellness needs (11%). Client satisfaction with mental health services was significantly higher among intervention participants, compared with control participants, at both follow-ups. CONCLUSIONS: The budget-neutral self-directed care model achieved superior client outcomes and greater satisfaction with mental health care, compared with services as usual.

A Mixed-Effects Model for Detecting Disrupted Connectivities in Heterogeneous Data.

The human brain is an amazingly complex network. Aberrant activities in this network can lead to various neurological disorders such as multiple sclerosis, Parkinson's disease, Alzheimer's disease, and autism. functional magnetic resonance imaging has emerged as an important tool to delineate the neural networks affected by such diseases, particularly autism. In this paper, we propose a special type of mixed-effects model together with an appropriate procedure for controlling false discoveries to detect disrupted connectivities for developing a neural network in whole brain studies. Results are illustrated with a large data set known as autism brain imaging data exchange which includes 361 subjects from eight medical centers.

Predicting Autism Spectrum Disorder Using Domain-Adaptive Cross-Site Evaluation.

The advances in neuroimaging methods reveal that resting-state functional fMRI (rs-fMRI) connectivity measures can be potential diagnostic biomarkers for autism spectrum disorder (ASD). Recent data sharing projects help us replicating the robustness of these biomarkers in different acquisition conditions or preprocessing steps across larger numbers of individuals or sites. It is necessary to validate the previous results by using data from multiple sites by diminishing the site variations. We investigated partial least square regression (PLS), a domain adaptive method to adjust the effects of multicenter acquisition. A sparse Multivariate Pattern Analysis (MVVPA) framework in a leave one site out cross validation (LOSOCV) setting has been proposed to discriminate ASD from healthy controls using data from six sites in the Autism Brain Imaging Data Exchange (ABIDE). Classification features were obtained using 42 bilateral Brodmann areas without presupposing any prior hypothesis. Our results showed that using PLS, SVM showed poorer accuracies with highest accuracy achieved (62%) than without PLS but not significantly. The regions occurred in two or more informative connections are Dorsolateral Prefrontal Cortex, Somatosensory Association Cortex, Primary Auditory Cortex, Inferior Temporal Gyrus and Temporopolar area. These interrupted regions are involved in executive function, speech, visual perception, sense and language which are associated with ASD. Our findings may support early clinical diagnosis or risk determination by identifying neurobiological markers to distinguish between ASD and healthy controls.

Sample size determination for multilevel hierarchical designs using generalized linear mixed models.

A unified statistical methodology of sample size determination is developed for hierarchical designs that are frequently used in many areas, particularly in medical and health research studies. The solid foundation of the proposed methodology opens a new horizon for power analysis in presence of various conditions. Important features such as joint significance testing, unequal allocations of clusters across intervention groups, and differential attrition rates over follow up time points are integrated to address some useful questions that investigators often encounter while conducting such studies. Proposed methodology is shown to perform well in terms of maintaining type I error rates and achieving the target power under various conditions. Proposed method is also shown to be robust with respect to violation of distributional assumptions of random-effects.