Selection, optimization and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse US populations.

Polygenic risk scores (PRSs) have improved in predictive performance, but several challenges remain to be addressed before PRSs can be implemented in the clinic, including reduced predictive performance of PRSs in diverse populations, and the interpretation and communication of genetic results to both providers and patients. To address these challenges, the National Human Genome Research Institute-funded Electronic Medical Records and Genomics (eMERGE) Network has developed a framework and pipeline for return of a PRS-based genome-informed risk assessment to 25,000 diverse adults and children as part of a clinical study. From an initial list of 23 conditions, ten were selected for implementation based on PRS performance, medical actionability and potential clinical utility, including cardiometabolic diseases and cancer. Standardized metrics were considered in the selection process, with additional consideration given to strength of evidence in African and Hispanic populations. We then developed a pipeline for clinical PRS implementation (score transfer to a clinical laboratory, validation and verification of score performance), and used genetic ancestry to calibrate PRS mean and variance, utilizing genetically diverse data from 13,475 participants of the All of Us Research Program cohort to train and test model parameters. Finally, we created a framework for regulatory compliance and developed a PRS clinical report for return to providers and for inclusion in an additional genome-informed risk assessment. The initial experience from eMERGE can inform the approach needed to implement PRS-based testing in diverse clinical settings.

Clinical Efficacy and Whole-Exome Sequencing of Liquid Biopsies in a Phase IB/II Study of Bazedoxifene and Palbociclib in Advanced Hormone Receptor-Positive Breast Cancer.

PURPOSE: Sensitivity to endocrine therapy (ET) is critical for the clinical benefit from the combination of palbociclib plus ET in hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer. Bazedoxifene is a third-generation selective estrogen receptor (ER) modulator and selective ER degrader with activity in preclinical models of endocrine-resistant breast cancer, including models harboring ESR1 mutations. Clinical trials in healthy women showed that bazedoxifene is well tolerated. PATIENTS AND METHODS: We conducted a phase Ib/II study of bazedoxifene plus palbociclib in patients with HR+/HER2- advanced breast cancer who progressed on prior ET (N = 36; NCT02448771). RESULTS: The study met its primary endpoint, with a clinical benefit rate of 33.3%, and the safety profile was consistent with what has previously been seen with palbociclib monotherapy. The median progression-free survival (PFS) was 3.6 months [95% confidence interval (CI), 2.0-7.2]. An activating PIK3CA mutation at baseline was associated with a shorter PFS (HR = 4.4; 95% CI, 1.5-13; P = 0.0026), but activating ESR1 mutations did not impact the PFS. Longitudinal plasma circulating tumor DNA whole-exome sequencing (WES; N = 68 plasma samples) provided an overview of the tumor heterogeneity and the subclonal genetic evolution, and identified actionable mutations acquired during treatment. CONCLUSIONS: The combination of palbociclib and bazedoxifene has clinical efficacy and an acceptable safety profile in a heavily pretreated patient population with advanced HR+/HER2- breast cancer. These results merit continued investigation of bazedoxifene in breast cancer.

Inverting the model of genomics data sharing with the NHGRI Genomic Data Science Analysis, Visualization, and Informatics Lab-space.

The NHGRI Genomic Data Science Analysis, Visualization, and Informatics Lab-space (AnVIL; https://anvilproject.org) was developed to address a widespread community need for a unified computing environment for genomics data storage, management, and analysis. In this perspective, we present AnVIL, describe its ecosystem and interoperability with other platforms, and highlight how this platform and associated initiatives contribute to improved genomic data sharing efforts. The AnVIL is a federated cloud platform designed to manage and store genomics and related data, enable population-scale analysis, and facilitate collaboration through the sharing of data, code, and analysis results. By inverting the traditional model of data sharing, the AnVIL eliminates the need for data movement while also adding security measures for active threat detection and monitoring and provides scalable, shared computing resources for any researcher. We describe the core data management and analysis components of the AnVIL, which currently consists of Terra, Gen3, Galaxy, RStudio/Bioconductor, Dockstore, and Jupyter, and describe several flagship genomics datasets available within the AnVIL. We continue to extend and innovate the AnVIL ecosystem by implementing new capabilities, including mechanisms for interoperability and responsible data sharing, while streamlining access management. The AnVIL opens many new opportunities for analysis, collaboration, and data sharing that are needed to drive research and to make discoveries through the joint analysis of hundreds of thousands to millions of genomes along with associated clinical and molecular data types.

Randomized prospective evaluation of genome sequencing versus standard-of-care as a first molecular diagnostic test.

PURPOSE: To evaluate the diagnostic yield and clinical relevance of clinical genome sequencing (cGS) as a first genetic test for patients with suspected monogenic disorders. METHODS: We conducted a prospective randomized study with pediatric and adult patients recruited from genetics clinics at Massachusetts General Hospital who were undergoing planned genetic testing. Participants were randomized into two groups: standard-of-care genetic testing (SOC) only or SOC and cGS. RESULTS: Two hundred four participants were enrolled, 202 were randomized to one of the intervention arms, and 99 received cGS. In total, cGS returned 16 molecular diagnoses that fully or partially explained the indication for testing in 16 individuals (16.2% of the cohort, 95% confidence interval [CI] 8.9-23.4%), which was not significantly different from SOC (18.2%, 95% CI 10.6-25.8%, P = 0.71). An additional eight molecular diagnoses reported by cGS had uncertain relevance to the participant's phenotype. Nevertheless, referring providers considered 20/24 total cGS molecular diagnoses (83%) to be explanatory for clinical features or worthy of additional workup. CONCLUSION: cGS is technically suitable as a first genetic test. In our cohort, diagnostic yield was not significantly different from SOC. Further studies addressing other variant types and implementation challenges are needed to support feasibility and utility of broad-scale cGS adoption.

Cross-Site Concordance Evaluation of Tumor DNA and RNA Sequencing Platforms for the CIMAC-CIDC Network.

PURPOSE: Whole-exome (WES) and RNA sequencing (RNA-seq) are key components of cancer immunogenomic analyses. To evaluate the consistency of tumor WES and RNA-seq profiling platforms across different centers, the Cancer Immune Monitoring and Analysis Centers (CIMAC) and the Cancer Immunologic Data Commons (CIDC) conducted a systematic harmonization study. EXPERIMENTAL DESIGN: DNA and RNA were centrally extracted from fresh frozen and formalin-fixed paraffin-embedded non-small cell lung carcinoma tumors and distributed to three centers for WES and RNA-seq profiling. In addition, two 10-plex HapMap cell line pools with known mutations were used to evaluate the accuracy of the WES platforms. RESULTS: The WES platforms achieved high precision (> 0.98) and recall (> 0.87) on the HapMap pools when evaluated on loci using > 50× common coverage. Nonsynonymous mutations clustered by tumor sample, achieving an index of specific agreement above 0.67 among replicates, centers, and sample processing. A DV200 > 24% for RNA, as a putative presequencing RNA quality control (QC) metric, was found to be a reliable threshold for generating consistent expression readouts in RNA-seq and NanoString data. MedTIN > 30 was likewise assessed as a reliable RNA-seq QC metric, above which samples from the same tumor across replicates, centers, and sample processing runs could be robustly clustered and HLA typing, immune infiltration, and immune repertoire inference could be performed. CONCLUSIONS: The CIMAC collaborating laboratory platforms effectively generated consistent WES and RNA-seq data and enable robust cross-trial comparisons and meta-analyses of highly complex immuno-oncology biomarker data across the NCI CIMAC-CIDC Network.

Rare Genetic Variants Associated With Sudden Cardiac Death in Adults.

BACKGROUND: Sudden cardiac death occurs in ∼220,000 U.S. adults annually, the majority of whom have no prior symptoms or cardiovascular diagnosis. Rare pathogenic DNA variants in any of 49 genes can pre-dispose to 4 important causes of sudden cardiac death: cardiomyopathy, coronary artery disease, inherited arrhythmia syndrome, and aortopathy or aortic dissection. OBJECTIVES: This study assessed the prevalence of rare pathogenic variants in sudden cardiac death cases versus controls, and the prevalence and clinical importance of such mutations in an asymptomatic adult population. METHODS: The authors performed whole-exome sequencing in a case-control cohort of 600 adult-onset sudden cardiac death cases and 600 matched controls from 106,098 participants of 6 prospective cohort studies. Observed DNA sequence variants in any of 49 genes with known association to cardiovascular disease were classified as pathogenic or likely pathogenic by a clinical laboratory geneticist blinded to case status. In an independent population of 4,525 asymptomatic adult participants of a prospective cohort study, the authors performed whole-genome sequencing and determined the prevalence of pathogenic or likely pathogenic variants and prospective association with cardiovascular death. RESULTS: Among the 1,200 sudden cardiac death cases and controls, the authors identified 5,178 genetic variants and classified 14 as pathogenic or likely pathogenic. These 14 variants were present in 15 individuals, all of whom had experienced sudden cardiac death-corresponding to a pathogenic variant prevalence of 2.5% in cases and 0% in controls (p < 0.0001). Among the 4,525 participants of the prospective cohort study, 41 (0.9%) carried a pathogenic or likely pathogenic variant and these individuals had 3.24-fold higher risk of cardiovascular death over a median follow-up of 14.3 years (p = 0.02). CONCLUSIONS: Gene sequencing identifies a pathogenic or likely pathogenic variant in a small but potentially important subset of adults experiencing sudden cardiac death; these variants are present in ∼1% of asymptomatic adults.

Early psychotherapeutic empathy, alliance, and client outcome: Preliminary evidence of indirect effects.

The association between psychotherapeutic empathy and client outcome is well established, yet the mechanisms underlying this association remain poorly understood. We hypothesized that early experiences of empathy influence outcome through the working alliance. To test this hypothesis, we used archival data collected from 56 clients (mean [M] age = 19.5 years, 83.9% female, 76.8% White) who reported mild, moderate, or severe depressive symptoms at screening and pretreatment assessments and then received five sessions of evidence-based psychotherapy. Therapists (M age = 26.0 years, 50% female, 100% White) were six students in a clinical psychology PhD program. Results of bootstrap analyses were consistent with the idea that early experiences of empathy strengthen the alliance (specifically the goals and tasks facets), which in turn facilitates improvements in depressive symptoms and psychological well-being. While preliminary, these results implicate a specific pathway of change in the treatment of depression.

Does the supervisor's teaching style influence the supervisee's learning prescribed techniques?

OBJECTIVES: This study examined the directive and non-directive supervisors' instructional styles, supervisees' interactive communications within supervision sessions as well as the relative success of supervisees' learning to apply specific techniques within psychotherapy. METHOD: The developers of Time-Limited Dynamic Psychotherapy (TLDP) provided the supervised training for 16 therapists as part of the "Vanderbilt II" psychotherapy project. Supervision sessions were rated for supervisors' adherence to TLDP content. Both supervisors and supervisee were rated for classroom interactive behaviors of "initiation" speech (e.g., introducing ideas) and "responsive" speech (e.g., amplifying the other speaker's topic). The third therapy session was targeted for discussion within supervision. Therapy sessions immediately before and after supervision were rated on TLDP adherence. RESULTS: One of the supervisors (Supervisor A) was found to use an instructional style of relatively more initiation-based speech, whereas the other (Supervisor B) used more response-based speech. Technical adherence for supervisees of Supervisor A was significantly higher than those assigned to Supervisor B. Supervisees' initiation-based speech during supervision predicted less use of TLDP techniques in the therapy session after supervision. Supervisors' interactive style was not associated with therapy adherence. CONCLUSIONS: Relatively more directive and structured supervision may influence the acquisition and use of manual-prescribed therapy techniques.

A prospective study of therapist facilitative interpersonal skills as a predictor of treatment outcome.

OBJECTIVE: This study examined whether therapists' facilitative interpersonal skills (FIS) would prospectively predict the outcomes of therapies that occurred more than one year later. METHOD: Therapists were 44 clinical psychology trainees who completed the FIS performance task and a self-reported measure of social skills in the initial weeks of their training. In the FIS task, prospective therapists were presented with a standard set of videos portraying clients in therapy. Verbal responses to these therapeutic simulations were recorded and then rated by trained coders. More than one year later, the therapists began providing psychotherapy to clients in a psychology clinic. Clients completed a symptom measure before each therapy session. RESULTS: Using multilevel modeling, it was found that therapist FIS significantly predicted client symptom change. That is, higher FIS therapists were more effective than lower FIS therapists. However, subsequent analyses showed that this FIS effect was not uniform across all therapy durations; specifically, higher FIS therapists were more effective than lower FIS therapists over shorter durations (e.g., ≤8 sessions) but did not differ from lower FIS therapists in effectiveness for the small percentage of therapies that were longer-term (e.g., >16 sessions). CONCLUSIONS: Therapists' interpersonal characteristics may influence client progress in therapy.

Clients' pretreatment role expectations, the therapeutic alliance, and clinical outcomes in outpatient therapy.

OBJECTIVES: The present study examined the associations between pretreatment role expectations, working alliance, and therapy outcome. A mediational model was hypothesized wherein the therapeutic alliance mediates the relationship between clients' pretreatment role expectations and psychotherapy outcome. METHOD: Sixty-eight clients completed the Expectations About Counseling-Brief Form at pretreatment, the Working Alliance Inventory-Short Form Revised after Session 3, and the Outcome Questionairre-45 at both pretreatment and the final session. RESULTS: All 3 expectations factors (Personal Commitment, Facilitative Conditions, Counselor Expertise) were related to the alliance. However, only expectations for Counselor Expertise were related to outcome, although this relationship did not appear to be mediated by the alliance. CONCLUSIONS: Suggested research directions, clinical implications, and study limitations are discussed.

Factorial and predictive validity of the expectations about counseling-brief (EAC-B) with clients seeking counseling.

Our goals in this study were to define the factorial structure of treatment expectations for a sample of treatment-seeking clients and to understand the predictive validity of those expectations. A sample of 353 clients who were about to begin counseling at a university counseling center or at a psychology clinic completed the Expectations About Counseling-Brief form (EAC-B) and then completed measures of the working alliance, session quality, and symptom distress throughout the treatment. Principal components analysis resulted in a 3-factor solution of EAC-B treatment expectations, which accounted for 48.0% of the total variance. Consistent with previous research, the 3 factors were labeled client involvement, counselor expertise, and facilitative conditions. Among clients with prior treatment experience, a meaningful 4-factor solution was achieved; it involved the counselor expertise factor being split into 2 subgroups labeled "counselor directive helping" and "counselor subjective expertise." The predictive validity of these 3 factors found that each of the 3 EAC-B factor-derived scales, as well the total EAC-B score, was predictive of clients' (but not therapists') ratings of the therapeutic alliance as well as ratings of session depth, smoothness, and positivity. Client involvement, facilitative conditions, and EAC-B Total score (but not counselor expertise) predicted therapy outcome.

The influence of supervision on manual adherence and therapeutic processes.

OBJECTIVES: To identify the effectiveness of psychotherapy supervision on therapists' immediate (next session) and long-term (1 year) adherence to time-limited dynamic psychotherapy (TLDP). METHOD: Sixteen therapists from the Vanderbilt II psychotherapy project were assigned new cases in pretraining, training, and booster/posttraining year-long cohorts. Technical adherence to the manual, as well as general therapeutic relational processes, were rated for clinical supervisory sessions in which the third therapy session was discussed. The therapy sessions immediately before and after the supervisory sessions were also rated for technical adherence and relational processes. RESULTS: Postsupervision adherence increased from the presupervision session during the training cohort. In supervision, therapists' discussion of techniques and strategies from the manual in supervision was significantly related to technical adherence in the session prior to (but not after) supervision. However, supervisors' discussion of specific techniques predicted therapists' total technical adherence in the therapy session after (but not before) supervision. In terms of the type of techniques, supervisors' influenced postsupervision therapy adherence on TLDP's unique approach to formulation, the cyclical maladaptive pattern, but did not influence technical adherence on the therapeutic relationship. CONCLUSIONS: In supervision, therapists tend to focus on how they adhered to techniques from the previous session, whereas supervisors' comments about specific techniques predicted how the therapist would adhere to techniques in the next therapy session. The findings provide support for the immediate effects of supervision in shaping therapist techniques as well as highlighting the challenges of altering common relational processes through technical training.

Working alliance as a mediator of client attachment dimensions and psychotherapy outcome.

Studies that employ multidimensional attachment measures to explore the impact of attachment style on psychotherapy process and outcome are virtually absent in the literature. Further, the role of the working (therapeutic) alliance as a mediator of the influence of attachment on treatment outcome has not been formally investigated. In order to address these gaps in the research, archival data from 66 psychotherapy clients treated at a university graduate program training clinic were used to examine the influence of three adult attachment dimensions (Comfort with Closeness, Comfort Depending on Others, and Rejection Anxiety) on the therapeutic alliance and outcome, as well as to assess whether the alliance mediates the relationship between attachment and therapy outcome. Both Comfort with Closeness and Comfort Depending on Others were significantly related to alliance and outcome, whereas Rejection Anxiety was not significantly related to either variable. Alliance was a significant partial mediator of the effect of Comfort with Closeness on outcome. The results suggest that multidimensional measures of attachment capture important influences on alliance and psychotherapy and that Comfort with Closeness promotes successful outcome by virtue of its influence on alliance.

Therapist effects: facilitative interpersonal skills as a predictor of therapist success.

This study examined sources of therapist effects in a sample of 25 therapists who saw 1,141 clients at a university counseling center. Clients completed the Outcome Questionnaire-45 (OQ-45) at each session. Therapists' facilitative interpersonal skills (FIS) were assessed with a performance task that measures therapists' interpersonal skills by rating therapist responses to video simulations of challenging client-therapist interactions. Therapists completed the Social Skills Inventory (SSI) and therapist demographic data (e.g., age, theoretical orientation) were available. To test for the presence of therapist effects and to examine the source(s) of these effects, data were analyzed with multilevel modeling. Of demographic predictor variables, only age accounted for therapist effects. The analysis with age, FIS, and SSI as predictors indicated that only FIS accounted for variance in outcomes suggesting that a portion of the variance in outcome between therapists is due to their ability to handle interpersonally challenging encounters with clients.

Clients' pretreatment counseling expectations as predictors of the working alliance.

Because research suggests that counseling expectations are malleable and that alliance ratings predict clinical outcomes, the relationship between this pretreatment client characteristic (expectations) and the quality of the alliance early in treatment deserves further attention. This study examined the relationships between 57 clients' pretreatment role expectations and 3rd-session client-rated alliance in a naturalistic setting. Prior to intake, clients completed the Expectations About Counseling-Brief Form (H. E. A. Tinsley, 1982), and clients completed the Working Alliance Inventory-Short Form Revised (R. L. Hatcher & J. A. Gillaspy, 2006) following the 3rd therapy session. Results indicate that clients' expectations for personal commitment predicted the task, bond, and goal dimensions of the alliance. Expectations for facilitative conditions and counselor expertise did not predict clients' perceptions of the alliance. Clinical implications and research directions are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved).