Correlates of suicidal behaviors and genetic risk among United States veterans with schizophrenia or bipolar I disorder.

Persons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at high risk for self-injurious behavior, suicidal ideation, and suicidal behaviors (SB). Characterizing associations between diagnosed health problems, prior pharmacological treatments, and polygenic scores (PGS) has potential to inform risk stratification. We examined self-reported SB and ideation using the Columbia Suicide Severity Rating Scale (C-SSRS) among 3,942 SCZ and 5,414 BPI patients receiving care within the Veterans Health Administration (VHA). These cross-sectional data were integrated with electronic health records (EHRs), and compared across lifetime diagnoses, treatment histories, follow-up screenings, and mortality data. PGS were constructed using available genomic data for related traits. Genome-wide association studies were performed to identify and prioritize specific loci. Only 20% of the veterans who reported SB had a corroborating ICD-9/10 EHR code. Among those without prior SB, more than 20% reported new-onset SB at follow-up. SB were associated with a range of additional clinical diagnoses, and with treatment with specific classes of psychotropic medications (e.g., antidepressants, antipsychotics, etc.). PGS for externalizing behaviors, smoking initiation, suicide attempt, and major depressive disorder were associated with SB. The GWAS for SB yielded no significant loci. Among individuals with a diagnosed mental illness, self-reported SB were strongly associated with clinical variables across several EHR domains. Analyses point to sequelae of substance-related and psychiatric comorbidities as strong correlates of prior and subsequent SB. Nonetheless, past SB was frequently not documented in health records, underscoring the value of regular screening with direct, in-person assessments, especially among high-risk individuals.

Communicating With Patients With Hearing Loss or Deafness-Can You Hear Me?

This Viewpoint explores the ideal safeguards to improve communication with patients who are deaf or hearing impaired.

Correlates of suicidal behaviors and genetic risk among United States veterans with schizophrenia or bipolar I disorder.

Objective: Persons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at high risk for self-injurious behavior, suicidal ideation, and suicidal behaviors (SB). Characterizing associations between diagnosed mental and physical health problems, prior pharmacological treatments, and aggregate genetic factors has potential to inform risk stratification and mitigation strategies. Methods: In this study of 3,942 SCZ and 5,414 BPI patients receiving VA care, self-reported SB and ideation were assessed using the Columbia Suicide Severity Rating Scale (C-SSRS). These cross-sectional data were integrated with electronic health records (EHR), and compared by lifetime diagnoses, treatment histories, follow-up screenings, and mortality data. Polygenic scores (PGS) for traits related to psychiatric disorders, substance use, and cognition were constructed using available genomic data, and exploratory genome-wide association studies were performed to identify and prioritize specific loci. Results: Only 20% of veterans who self-reported SB had a corroborating ICD-9/10 code in their EHR; and among those who denied prior behaviors, more than 20% reported new-onset SB at follow-up. SB were associated with a range of psychiatric and non-psychiatric diagnoses, and with treatment with specific classes of psychotropic medications (e.g., antidepressants, antipsychotics, etc.). PGS for externalizing behaviors, smoking, suicide attempt, and major depressive disorder were also associated with attempt and ideation. Conclusions: Among individuals with a diagnosed mental illness, a GWAS for SB did not yield any significant loci. Self-reported SB were strongly associated with clinical variables across several EHR domains. Overall, clinical and polygenic analyses point to sequelae of substance-use related behaviors and other psychiatric comorbidities as strong correlates of prior and subsequent SB. Nonetheless, past SB was frequently not documented in clinical settings, underscoring the value of regular screening based on direct, in-person assessments, especially among high-risk individuals.

Penetrance and Pleiotropy of Polygenic Risk Scores for Schizophrenia, Bipolar Disorder, and Depression Among Adults in the US Veterans Affairs Health Care System.

Importance: Serious mental illnesses, including schizophrenia, bipolar disorder, and depression, are heritable, highly multifactorial disorders and major causes of disability worldwide. Objective: To benchmark the penetrance of current neuropsychiatric polygenic risk scores (PRSs) in the Veterans Health Administration health care system and to explore associations between PRS and broad categories of human disease via phenome-wide association studies. Design, Setting, and Participants: Extensive Veterans Health Administration's electronic health records were assessed from October 1999 to January 2021, and an embedded cohort of 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder were found. The performance of schizophrenia, bipolar disorder, and major depression PRSs were compared in participants of African or European ancestry in the Million Veteran Program (approximately 400 000 individuals), and associations between PRSs and 1650 disease categories based on ICD-9/10 billing codes were explored. Last, genomic structural equation modeling was applied to derive novel PRSs indexing common and disorder-specific genetic factors. Analysis took place from January 2021 to January 2022. Main Outcomes and Measures: Diagnoses based on in-person structured clinical interviews were compared with ICD-9/10 billing codes. PRSs were constructed using summary statistics from genome-wide association studies of schizophrenia, bipolar disorder, and major depression. Results: Of 707 299 enrolled study participants, 459 667 were genotyped at the time of writing; 84 806 were of broadly African ancestry (mean [SD] age, 58 [12.1] years) and 314 909 were of broadly European ancestry (mean [SD] age, 66.4 [13.5] years). Among 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder, 8962 (95.6%) were correctly identified using ICD-9/10 codes (2 or more). Among those of European ancestry, PRSs were robustly associated with having received a diagnosis of schizophrenia (odds ratio [OR], 1.81 [95% CI, 1.76-1.87]; P < 10-257) or bipolar disorder (OR, 1.42 [95% CI, 1.39-1.44]; P < 10-295). Corresponding effect sizes in participants of African ancestry were considerably smaller for schizophrenia (OR, 1.35 [95% CI, 1.29-1.42]; P < 10-38) and bipolar disorder (OR, 1.16 [95% CI, 1.11-1.12]; P < 10-10). Neuropsychiatric PRSs were associated with increased risk for a range of psychiatric and physical health problems. Conclusions and Relevance: Using diagnoses confirmed by in-person structured clinical interviews and current neuropsychiatric PRSs, the validity of an electronic health records-based phenotyping approach in US veterans was demonstrated, highlighting the potential of PRSs for disentangling biological and mediated pleiotropy.

Returning Individual Research Results to Vulnerable Individuals.

Although issues associated with returning individual research results to study participants have been well explored, these issues have been less thoroughly investigated in vulnerable individuals and populations. Considerations regarding return of research results to these individuals and populations, including how best to ensure truly informed consent, how to minimize the risks and benefits of the return of research results, and how best to ensure justice may differ from those of the population at large. This article discusses the issues and challenges associated with the return of individual research results (such as genomic, proteomic, or other biomarker data) to potentially vulnerable individuals and populations, including those who may be vulnerable for cognitive, communicative, institutional, social, deferential, medical, economic, or social reasons. It explores factors that should be considered in the design, conduct, and oversight of ethically responsible research involving the return of research results to vulnerable individuals and populations and discuss recommendations for those engaged in this work.

Relative sensitivity of anterior nares and nasopharyngeal swabs for initial detection of SARS-CoV-2 in ambulatory patients: Rapid review and meta-analysis.

Nasopharyngeal (NP) swabs are considered "gold standard" for diagnosing SARS-CoV-2 infections, but anterior nares or mid-turbinate swabs (nasal swabs) are often used. We performed a meta-analysis comparing the sensitivity of nasal and nasopharyngeal swabs against a composite reference standard for the initial diagnosis of SARS-CoV-2 infection in ambulatory patients. The study is registered on PROSPERO (CRD42020221827). Data sources included studies appearing between January 1, 2020 and March 20, 2021, identified by searches of PubMed, medRxiv and bioRxiv. Studies included at least 20 subjects who simultaneously provided nasal and nasopharyngeal specimens for reverse transcription-polymerase chain reaction testing, and for which confusion matrices could be constructed. Authors individually assessed studies for inclusion and compared assessments. Each author independently extracted all data elements; differences were reconciled by review of initial data sources. Extracted data included specimen site, patient characteristics, collection site, and confusion matrices comparing results for nasal and nasopharyngeal swabs. Assessed against a composite reference standard, anterior nares swabs are less sensitive (82% - 88%) than nasopharyngeal swabs (98%). For populations with 10% specimen positivity, the negative predictive values of all swab types were greater than 98%. Mid-turbinate and anterior nares swabs seem to perform similarly. The lower sensitivity associated with nasal swab SARS-CoV-2 diagnosis is justified by the ability to screen more patients and reduced personal protective equipment requirements. Our conclusions are limited by the small number of studies and the significant heterogeneity of study designs and study outcomes.

Clinical trials proposed for the VA Cooperative Studies Program: Success rates and factors impacting approval.

The process by which funding organizations select among the myriad number of proposals they receive is a matter of significant concern for researchers and the public alike. Despite an extensive literature on the topic of peer review and publications on criteria by which clinical investigations are reviewed, publications analyzing peer review and other processes leading to government funding decisions on large multi-site clinical trials proposals are sparse. To partially address this gap, we reviewed the outcomes of scientific and programmatic evaluation for all letters of intent (LOIs) received by the Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) between July 4, 2008, and November 28, 2016. If accepted, these LOIs represented initial steps towards later full proposals that also underwent scientific peer review. Twenty-two of 87 LOIs were ultimately funded and executed as CSP projects, for an overall success rate of 25%. Most proposals which received a negative decision did so prior to submission of a full proposal. Common reasons for negative scientific review of LOIs included investigator inexperience, perceived lack of major scientific impact, lack of preliminary data and flawed or confused experimental design, while the most common reasons for negative reviews of final proposals included questions of scientific impact and issues of study design, including outcome measures, randomization, and stratification. Completed projects have been published in high impact clinical journals. Findings highlight several factors leading to successfully obtaining funding support for clinical trials. While our analysis is restricted to trials proposed for CSP, the similarities in review processes with those employed by the National Institutes of Health and the Patient Centered Outcomes Research Institute suggest the possibility that they may also be important in a broader context.

Optimal serum ferritin level range: iron status measure and inflammatory biomarker.

This report provides perspectives concerning dual roles of serum ferritin as a measure of both iron status and inflammation. We suggest benefits of a lower range of serum ferritin as has occurred for total serum cholesterol and fasting blood glucose levels. Observations during a prospective randomized study using phlebotomy in patients with peripheral arterial disease offered unique insights into dual roles of serum ferritin both as an iron status marker and acute phase reactant. Robust positive associations between serum ferritin, interleukin 6 [IL-6], tissue necrosis factor-alpha, and high sensitivity C-reactive protein were discovered. Elevated serum ferritin and IL-6 levels associated with increased mortality and with reduced mortality at ferritin levels <100 ng mL-1. Epidemiologic studies demonstrate similar outcomes. Extremely elevated ferritin and IL-6 levels also occur in individuals with high mortality due to SARS-CoV-2 infection. Disordered iron metabolism reflected by a high range of serum ferritin level signals disease severity and outcomes. Based upon experimental and epidemiologic data, we suggest testing the hypotheses that optimal ferritin levels for cardiovascular mortality reduction range from 20 to 100 ng mL-1 with % transferrin levels from 20 to 50%, to ensure adequate iron status and that ferritin levels above 194 ng mL-1 associate with all-cause mortality in population cohorts.

Relative Sensitivity of Saliva and Upper Airway Swabs for Initial Detection of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in Ambulatory Patients: Rapid Review.

Saliva has been proposed as an alternative to upper airway swabs when testing for severe acute respiratory syndrome coronavirus 2. Although some studies have suggested higher viral loads and clinical sensitivity when testing saliva, studies have been relatively small and have given rise to contradictory results. To better understand the relative performance characteristics of saliva and upper airway samples, I performed a rapid systematic review (registered on PROSPERO as CRD42020205035), focusing on studies that included at least 20 subjects who provided diagnostic saliva and upper airway samples on the same day, which were tested by nucleic acid amplification methods and for which a confusion matrix could be constructed for based on a composite reference standard. Nineteen studies comprising 21 cohorts that met predetermined acceptance criteria were identified following a search of PubMed, medRxiv, and bioRxiv. Seven of these cohorts were incorporated into a meta-analysis using a random effects model, which suggests that nasopharyngeal swabs are somewhat more sensitive than saliva samples for the diagnosis of early disease in ambulatory patients, such as in drive-through centers or community health centers. Nevertheless, the difference is modest, and the reduced need for personal protective equipment for saliva sampling may justify the difference. Conclusions are limited by the significant heterogeneity of disease prevalence in the study populations and variation in the approaches to saliva sample collection.

Genome-Wide Association Studies of Schizophrenia and Bipolar Disorder in a Diverse Cohort of US Veterans.

BACKGROUND: Schizophrenia (SCZ) and bipolar disorder (BIP) are debilitating neuropsychiatric disorders, collectively affecting 2% of the world's population. Recognizing the major impact of these psychiatric disorders on the psychosocial function of more than 200 000 US Veterans, the Department of Veterans Affairs (VA) recently completed genotyping of more than 8000 veterans with SCZ and BIP in the Cooperative Studies Program (CSP) #572. METHODS: We performed genome-wide association studies (GWAS) in CSP #572 and benchmarked the predictive value of polygenic risk scores (PRS) constructed from published findings. We combined our results with available summary statistics from several recent GWAS, realizing the largest and most diverse studies of these disorders to date. RESULTS: Our primary GWAS uncovered new associations between CHD7 variants and SCZ, and novel BIP associations with variants in Sortilin Related VPS10 Domain Containing Receptor 3 (SORCS3) and downstream of PCDH11X. Combining our results with published summary statistics for SCZ yielded 39 novel susceptibility loci including CRHR1, and we identified 10 additional findings for BIP (28 326 cases and 90 570 controls). PRS trained on published GWAS were significantly associated with case-control status among European American (P < 10-30) and African American (P < .0005) participants in CSP #572. CONCLUSIONS: We have demonstrated that published findings for SCZ and BIP are robustly generalizable to a diverse cohort of US veterans. Leveraging available summary statistics from GWAS of global populations, we report 52 new susceptibility loci and improved fine-mapping resolution for dozens of previously reported associations.

Testing for Severe Acute Respiratory Syndrome-Coronavirus 2: Challenges in Getting Good Specimens, Choosing the Right Test, and Interpreting the Results.

OBJECTIVES: We explore ways to reduce errors in laboratory diagnosis of severe acute respiratory syndrome-coronavirus 2 infection by considering preanalytic, analytic, and postanalytic sources. To address preanalytic challenges, we first consider alternative anatomic sites for specimen collection, then discuss self-collection, alternative sampling devices, and transport media. Strengths and limitations of various analytic test systems are considered in the context of postanalytic challenges associated with making test results meaningful, specifically considering the complex relationship between "positive" test results and reproduction and shedding of intact virus. Finally, we provide recommendations regarding healthcare worker surveillance and release of patients with coronavirus disease 2019 from isolation. DATA SOURCES: Material was derived from a Webinar available to the public, manufacturer's websites, U.S. Food and Drug Administration, and Centers for Disease Control and Prevention websites and from both peer-reviewed papers identified by PubMed search and nonpeer-reviewed papers posted on Biorxiv and Medrxiv. Unpublished data came from the Washington State Department of Health. STUDY SELECTION: We included studies that compared diagnostic performance strategies without introducing bias due to use of an imperfect gold standard. Case series and case reports were included as necessary to illuminate the significance of results. DATA EXTRACTION: Data were extracted manually. DATA SYNTHESIS: Sensitivity, specificity, and CIs were computed from article data using a composite reference standard. Nucleic acid-based tests were assumed to perform at 100% specificity. CONCLUSIONS: Although sputum and bronchoalveolar lavage samples provide the highest diagnostic sensitivity for severe acute respiratory syndrome-coronavirus 2, nasopharyngeal, mid turbinate, and nasal specimens are suitable in most cases and require less use of personal protective equipment. When desired sampling materials are unavailable, alternatives may be substituted with no loss of performance. Both reverse transcriptase polymerase chain reaction tests and rapid nucleic acid-based tests offer good performance in most circumstances. Testing is not required to release most patients from isolation.

Genotyping Array Design and Data Quality Control in the Million Veteran Program.

The Million Veteran Program (MVP), initiated by the Department of Veterans Affairs (VA), aims to collect biosamples with consent from at least one million veterans. Presently, blood samples have been collected from over 800,000 enrolled participants. The size and diversity of the MVP cohort, as well as the availability of extensive VA electronic health records, make it a promising resource for precision medicine. MVP is conducting array-based genotyping to provide a genome-wide scan of the entire cohort, in parallel with whole-genome sequencing, methylation, and other 'omics assays. Here, we present the design and performance of the MVP 1.0 custom Axiom array, which was designed and developed as a single assay to be used across the multi-ethnic MVP cohort. A unified genetic quality-control analysis was developed and conducted on an initial tranche of 485,856 individuals, leading to a high-quality dataset of 459,777 unique individuals. 668,418 genetic markers passed quality control and showed high-quality genotypes not only on common variants but also on rare variants. We confirmed that, with non-European individuals making up nearly 30%, MVP's substantial ancestral diversity surpasses that of other large biobanks. We also demonstrated the quality of the MVP dataset by replicating established genetic associations with height in European Americans and African Americans ancestries. This current dataset has been made available to approved MVP researchers for genome-wide association studies and other downstream analyses. Further data releases will be available for analysis as recruitment at the VA continues and the cohort expands both in size and diversity.

Return of Individual Research Results: A Guide for Biomedical Researchers Utilizing Human Biospecimens.

The recent movement toward returning individual research results to study subjects/participants generates ethical and legal challenges for laboratories performing research on human biospecimens. The concept of an individual's interest in knowing the results of testing on their tissue is pitted against individual and systemic risks and an established legal framework regulating the performance of laboratory testing for medical care purposes. This article discusses the rationale for returning individual research results to subjects, the potential risks associated with returning these results, and the legal framework in the United States that governs testing of identifiable human biospecimens. On the basis of these considerations, this article provides recommendations for investigators to consider when planning and executing human biospecimen research, with the objective of appropriately balancing the interests of research subjects, the need for ensuring integrity of the research process, and compliance with US laws and regulations.

Genome-wide association study of cognitive performance in U.S. veterans with schizophrenia or bipolar disorder.

Cognitive impairment is a frequent and serious problem in patients with various forms of severe mental illnesses (SMI), including schizophrenia (SZ) and bipolar disorder (BP). Recent research suggests genetic links to several cognitive phenotypes in both SMI and in the general population. Our goal in this study was to identify potential genomic signatures of cognitive functioning in veterans with severe mental illness and compare them to previous findings for cognition across different populations. Veterans Affairs (VA) Cooperative Studies Program (CSP) Study #572 evaluated cognitive and functional capacity measures among SZ and BP patients. In conjunction with the VA Million Veteran Program, 3,959 European American (1,095 SZ, 2,864 BP) and 2,601 African American (1,095 SZ, 2,864 BP) patients were genotyped using a custom Affymetrix Axiom Biobank array. We performed a genome-wide association study of global cognitive functioning, constructed polygenic scores for SZ and cognition in the general population, and examined genetic correlations with 2,626 UK Biobank traits. Although no single locus attained genome-wide significance, observed allelic effects were strongly consistent with previous studies. We observed robust associations between global cognitive functioning and polygenic scores for cognitive performance, intelligence, and SZ risk. We also identified significant genetic correlations with several cognition-related traits in UK Biobank. In a diverse cohort of U.S. veterans with SZ or BP, we demonstrate broad overlap of common genetic effects on cognition in the general population, and find that greater polygenic loading for SZ risk is associated with poorer cognitive performance.

The Journal of Molecular Diagnostics: 20 Years of Clinical Innovation.

This guest editorial highlights 20 years of clinical innovation in JMD.

Gender Differences in Demographic and Health Characteristics of the Million Veteran Program Cohort.

BACKGROUND: The Department of Veterans Affairs Million Veteran Program (MVP) is the largest ongoing cohort program of its kind, with 654,903 enrollees as of June 2018. The objectives of this study were to examine gender differences in the MVP cohort with respect to response and enrollment rates; demographic, health, and health care characteristics; and prevalence of self-reported health conditions. METHODS: The MVP Baseline Survey was completed by 415,694 veterans (8% women), providing self-report measures of demographic characteristics, health status, and medical history. RESULTS: Relative to men, women demonstrated a higher positive responder rate (23.0% vs. 16.0%), slightly higher enrollment rate (13.5% vs. 12.9%), and, among enrollees, a lower survey completion rate (59.7% vs. 63.8%). Women were younger, more racially diverse, had higher educational attainment, and were less likely to be married or cohabitating with a partner than men. Women were more likely to report good to excellent health status but poorer physical fitness, and less likely to report lifetime smoking and drinking than men. Compared with men, women veterans showed an increased prevalence of musculoskeletal conditions, thyroid problems, gastrointestinal conditions, migraine headaches, and mental health disorders, as well as a decreased prevalence of gout, cardiovascular diseases, high cholesterol, diabetes, and hearing problems. CONCLUSIONS: These results revealed some substantial gender differences in the research participation rates, demographic profile, health characteristics, and prevalence of health conditions for veterans in the MVP cohort. Findings highlight the need for tailoring recruitment efforts to ensure representation of the increasing women veteran population receiving care through the Veterans Health Administration.

PREVALENCE OF PARELAPHOSTRONGYLUS ANDERSONI IN WHITE-TAILED DEER, OTHER CERVIDS, AND BOVIDS IN NORTHERN FLORIDA.

Parelaphostrongylus andersoni, the muscleworm, commonly infects white-tailed deer (Odocoileus virginianus) and also infects caribou (Rangifer tarandus [R.t.] groenlanicus, R.t. grantii, R.t. tarandus, and R.t. caribou). Heavy infection with P. andersoni leads to weakness in the hindquarters, abnormal gait, and pulmonary lesions. The geographical range and full host spectrum of this parasite are not fully known. This study aims to understand host specificity better, especially in nonnative cervids and bovids. This study involved the collection of 140 fecal samples from native and nonnative cervid and bovid species, and 34 snail specimens. With the use of real-time PCR, we found 4/47 (8.5%) O. virginianus fecal samples were positive for P. andersoni. No previously undocumented species of cervids or bovids were found to be infected. Further research is warranted to understand P. andersoni range, host distribution, and potential impact on host health.

Colonoscopy vs. Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM): Rationale for Study Design.

RATIONALE: Colorectal cancer (CRC) is preventable through screening, with colonoscopy and fecal occult blood testing comprising the two most commonly used screening tests. Given the differences in complexity, risk, and cost, it is important to understand these tests' comparative effectiveness. STUDY DESIGN: The CONFIRM Study is a large, pragmatic, multicenter, randomized, parallel group trial to compare screening with colonoscopy vs. the annual fecal immunochemical test (FIT) in 50,000 average risk individuals. CONFIRM examines whether screening colonoscopy will be superior to a FIT-based screening program in the prevention of CRC mortality measured over 10 years. Eligible individuals 50-75 years of age and due for CRC screening are recruited from 46 Veterans Affairs (VA) medical centers. Participants are randomized to either colonoscopy or annual FIT. Results of colonoscopy are managed as per usual care and study participants are assessed for complications. Participants testing FIT positive are referred for colonoscopy. Participants are surveyed annually to determine if they have undergone colonoscopy or been diagnosed with CRC. The primary endpoint is CRC mortality. The secondary endpoints are (1) CRC incidence (2) complications of screening colonoscopy, and (3) the association between colonoscopists' characteristics and neoplasia detection, complications and post-colonoscopy CRC. CONFIRM leverages several key characteristics of the VA's integrated healthcare system, including a shared medical record with national databases, electronic CRC screening reminders, and a robust national research infrastructure with experience in conducting large-scale clinical trials. When completed, CONFIRM will be the largest intervention trial conducted within the VA (ClinicalTrials.gov identifier: NCT01239082).