Infectious etiologies among post-donation deferrals in a military blood donation center.

BACKGROUND: The burden of transfusion-transmitted infections among blood recipients remains low due to extensive pre- and post-donation screening. However, the military has the unique challenge of providing blood in austere environments with limited testing capabilities. This study evaluates the infectious etiologies of deferred blood donors at a large military blood donation center. METHODS: All blood donors at the Armed Service Blood Bank Center, San Antonio, between 2017 and 2022 with positive post-donation screening for hepatitis C (HCV), hepatitis B (HBV), human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV-I/II), Zika (2018-2021), West Nile virus, Trypanosoma cruzi, Treponema pallidum, or Babesia microti (2020-2022) were evaluated. Donors were deferred based on Food and Drug Administration (FDA) guidance. RESULTS: Two-hundred and thirteen (213) donors met FDA criteria for deferral. T. pallidum (n = 45, 50.3 per 100,000), HCV (n = 34, 38.0 per 100,000), and HBV (n = 19, 21.2 per 100,000) were the most common pathogens among those with both positive screening and confirmatory testing. The majority of HIV (95%), Chagas (78%), HTLV-I/II (50%) deferrals were due to indeterminate confirmatory tests following initial positive screens. The majority of deferrals for HBV were for a second occurrence of a positive screen despite negative confirmatory testing. CONCLUSION: The rates of post-donation deferral for transfusion-transmissible infections were low in this military cohort. Our findings suggest that donor testing in deployed service members should focus on HBV, HCV, and T. pallidum and highlight the need for better diagnostics for HIV, Chagas, and HTLV-I/II.

Place-Based Developmental Research: Conceptual and Methodological Advances in Studying Youth Development in Context.

Scientists have, for some time, recognized that development unfolds in numerous settings, including families, schools, neighborhoods, and organized and unorganized activity settings. Since the turn of the 20th century, the body of mainstream neighborhood effects scholarship draws heavily from the early 20th century Chicago School of Sociology frameworks and have been situating development in neighborhood contexts and working to identify the structures and processes via which neighborhoods matter for a range of developmental outcomes, especially achievement, behavioral and emotional problems, and sexual activity. From this body of work, two new areas of developmental scholarship are emerging. Both areas are promising for advancing an understanding of child development in context. First, cultural-developmental neighborhood researchers are advancing neighborhood effects research that explicitly recognizes the ways that racial, ethnic, cultural, and immigrant social positions matter for neighborhood environments and for youths' developmental demands, affordances, experiences, and competencies. This body of work substantially expands the range of developmental outcomes examined in neighborhood effects scholarship to recognize normative physical, emotional, cognitive, behavioral, social, and cultural competencies that have largely been overlooked in neighborhood effects scholarship that espoused a more color-blind developmental approach. Second, activity space neighborhood researchers are recognizing that residential neighborhoods have important implications for broader activity spaces-or the set of locations and settings to which youth are regularly exposed, including, for example, schools, work, organized activities, and hang-outs. They are using newer technologies and geographic frameworks to assess exposure to residential neighborhood and extra-neighborhood environments. These perspectives recognize that time (i.e., from microtime to mesotime) and place are critically bound and that exposures can be operationalized at numerous levels of the ecological system (i.e., from microsystems to macrosystems). These frameworks address important limitations of prior development in context scholarship by addressing selection and exposure. Addressing selection involves recognizing that families have some degree of choice when selecting into settings and variables that predict families' choices (e.g., income) also predict development. Considering exposure involves recognizing that different participants or residents experience different amounts of shared and nonshared exposures, resulting in both under-and over-estimation of contextual effects. Activity space scholars incorporate exposure to the residential neighborhood environments, but also to other locations and settings to which youth are regularly exposed, like schools, after-school settings, work, and hang-outs. Unfortunately, the cultural-development and activity space streams, which have both emerged from early 20th century work on neighborhood effects on development, have been advancing largely independently. Thus, the overarching aim of this monograph is to integrate scholarship on residential neighborhoods, cultural development, and activity spaces to advance a framework that can support a better understanding of development in context for diverse groups. In Chapters I and II we present the historical context of the three streams of theoretical, conceptual, and methodological research. We also advance a comprehensive cultural-developmental activity space framework for studying development in context among children, youth, and families that are ethnically, racially, and culturally heterogeneous. This framework actively recognized diversity in ethnic, racial, immigrant, and socioeconomic social positions. In Chapters III-V we advance specific features of the framework, focusing on: (1) the different levels of nested and nonnested ecological systems that can be captured and operationalized with activity space methods, (2) the different dimensions of time and exposures or experiences that can be captured and operationalized by activity space methods, and (3) the importance of settings structures and social processes for identifying underlying mechanisms of contextual effects on development. Structures are setting features related to the composition and spatial arrangement of people and institutions (e.g., socioeconomic disadvantage, ethnic/racial compositions). Social processes represent the collective social dynamics that take place in settings, like social interactions, group activities, experiences with local institutions, mechanisms of social control, or shared beliefs. In Chapter VI, we highlight a range of methodological and empirical exemplars from the United States that are informed by our comprehensive cultural-developmental activity space framework. These exemplars feature both quantitative and qualitative methods, including method mixing. These exemplars feature both quantitative and qualitative methods, including method mixing. The exemplars also highlight the application of the framework across four different samples from populations that vary in terms of race, ethnicity, gender, age, socioeconomic status (SES), geographic region, and urbanicity. They capture activity space characteristics and features in a variety of ways, in addition to incorporating family shared and nonshared activity space exposures. Finally, in Chapter VII we summarize the contributions of the framework for advancing a more comprehensive science of development in context, one that better realizes major developmental theories emphasizing persons, processes, contexts, and time. Additionally, we offer a place-based, culturally informed developmental research agenda to meet the needs of an increasingly diverse population.

"My Plate is Full": Reasons for Declining a Genetic Evaluation of Hearing Loss.

The aim of this study was to obtain patient and parent perspectives on genetic evaluation of hearing loss, in order to identify motivators, expectations, and barriers. Three focus groups were conducted following a semi-structured discussion guide, led by an independent moderator. Participants were hearing parents of children with permanent hearing loss or deaf adults. Qualitative content analysis was used to develop a codebook and identify major themes and subthemes. Participant views were compared to national guidelines. The 28 participants comprised 23 parents representing 21 unique families and 5 deaf adults. 13/21 families and 0/5 adults reported comorbidities, 4/21 families and 3/5 adults had a positive family history, and 12/21 families versus 0/5 adults had utilized genetics services. A common theme among adults and parents was a curiosity as to the cause of hearing loss. Parents were motivated to detect comorbidities and optimize care for hearing loss. Some parents felt overwhelmed by the hearing loss and unprepared to pursue early genetic evaluation as recommended in guidelines. Several reported positive experiences following genetics consultation, while others reported unease and unmet expectations. Notably, both parents and adults expressed ambivalence regarding the desire for genetic knowledge. Financial concerns and difficulties obtaining a referral were cited as extrinsic barriers. For parents of children with hearing loss, both the presence of comorbidities and a positive family history were drivers of genetics consultation and/or genetic testing. We identified educational opportunities for both patients and providers that would improve informed decision-making and increase access to genetic services. Consideration of the patient/family perspective and their decision-making processes, along with flexibility in the approach to genetics evaluation and its timing, will optimize both the development and implementation of guidelines.

COVID-19 Booster Vaccination in the U.S. Military, August 2021-January 2022.

INTRODUCTION: A booster dose of messenger RNA vaccine protects against severe COVID-19 outcomes. This study examined the incidence of COVID-19 booster vaccination among active-duty U.S. military servicemembers between August 2021 and January 2022, factors associated with vaccination uptake, and trends over time. METHODS: This was a retrospective cohort study of active-duty military personnel using data from the Defense Medical Surveillance System. Participants were included if they served in the active component from August 2021 through January 2022 and were eligible to receive a COVID-19 booster dose by January 2022. Adjusted hazard ratio estimates of time to booster vaccination were calculated using Cox proportional hazards regression. RESULTS: Lower booster vaccine uptake was seen in the U.S. military (25%) than among the general U.S. population at the same time (45%). Booster vaccination increased with older age, with greater education, with higher income, among women, and among those stationed overseas; it decreased with previous COVID-19 infection and use of the Janssen vaccine. There were no significant racial or ethnic disparities in booster vaccination. CONCLUSIONS: In the absence of a compulsory vaccination policy, lower booster vaccine uptake was seen among servicemembers than among the general U.S. population, particularly among members who were younger, were male, Marines, and had a previous history of infection. Low vaccination rates not only increase the risk of acute and long-term health effects from COVID-19 among servicemembers, but they also degrade the overall readiness of the U.S. military.

Clinically Actionable Findings Derived From Predictive Genomic Testing Offered in a Medical Practice Setting.

OBJECTIVE: To assess the presence of clinically actionable results and other genetic findings in an otherwise healthy population of adults seen in a medical practice setting and offered "predictive" genomic testing. PATIENTS AND METHODS: In 2014, a predictive genomics clinic for generally healthy adults was launched through the Mayo Clinic Executive Health Program. Self-identified interested patients met with a genomic nurse and genetic counselor for pretest advice and education. Two genome sequencing platforms and one gene panel-based health screen were offered. Posttest genetic counseling was available for patients who elected testing. From March 1, 2014, through June 1, 2019, 1281 patients were seen and 301 (23.5%) chose testing. Uptake rates increased to 36.3% [70 of 193]) in 2019 from 11.8% [2 of 17] in 2014. Clinically actionable results and genetic findings were analyzed using descriptive statistics. RESULTS: Clinically actionable results were detected in 11.6% of patients (35 of 301), and of those, 51.7% (15 of 29) with a cancer or cardiovascular result = did not have a personal or family history concerning for a hereditary disorder. The most common actionable results were in the BCHE, BRCA2, CHEK2, LDLR, MUTYH, and MYH7 genes. A carrier of at least one recessive condition was found in 53.8% of patients (162 of 301). At least one variant associated with multifactorial disease was found in 44.5% (134 of 301) (eg, 25 patients were heterozygous for the F5 factor V Leiden variant associated with thrombophilia risk). CONCLUSION: Our predictive screening revealed that 11.6% of individuals will test positive for a clinically actionable, likely pathogenic/pathogenic variant. This finding suggests that wider knowledge and adoption of predictive genomic services could be beneficial in medical practice, although additional studies are needed.

Assessing the stability of biobank donor preferences regarding sample use: evidence supporting the value of dynamic consent.

Dynamic consent has been proposed as a strategy for addressing the limitations of traditional, broad consent for biobank participation. Although the argument for dynamic consent has been made on theoretical grounds, empirical studies evaluating the potential utility of dynamic consent are needed to enhance deliberations about the merits of dynamic consent. Few studies have assessed such considerations as whether donor preferences may change over time or if participants would use a dynamic consent mechanism to modify preferences when they change. We administered a 66-item survey to participants in a large DNA biobank. The survey sought to gauge the stability of donor preferences specified at the time of biobank enrollment, specifically the stability of donors' preference regarding posthumous availability of biospecimens to next-of-kin. We received 1164 completed surveys for a response rate of 72%. Forty percent of respondents indicated a preference regarding sample availability on the survey (T2) that was inconsistent with the preference they had expressed when they enrolled in the biobank (T1). Most (94%) individuals with inconsistent preferences regarding sample availability had initially restricted sample availability at T1 but were comfortable with broader availability when asked at the time of the survey (T2). Our findings demonstrate that preferences regarding sample use expressed at the time of enrollment in a DNA biobank may not be reliable indicators of donor preferences over time. These findings lend empirical support to the case for a dynamic consent model in which biobank participants are approached over time to clarify their views regarding sample use.

Challenges in returning results in a genomic medicine implementation study: the Return of Actionable Variants Empirical (RAVE) study.

To inform the process of returning results in genome sequencing studies, we conducted a quantitative and qualitative assessment of challenges encountered during the Return of Actionable Variants Empiric (RAVE) study conducted at Mayo Clinic. Participants (n = 2535, mean age 63 ± 7, 57% female) were sequenced for 68 clinically actionable genes and 14 single nucleotide variants. Of 122 actionable results detected, 118 were returnable; results were returned by a genetic counselor-86 in-person and 12 by phone. Challenges in returning actionable results were encountered in a significant proportion (38%) of the cohort and were related to sequencing and participant contact. Sequencing related challenges (n = 14), affecting 13 participants, included reports revised based on clinical presentation (n = 3); reports requiring corrections (n = 2); mosaicism requiring alternative DNA samples for confirmation (n = 3); and variant re-interpretation due to updated informatics pipelines (n = 6). Participant contact related challenges (n = 44), affecting 38 participants, included nonresponders (n = 20), decedents (n = 1), and previously known results (n = 23). These results should be helpful to investigators preparing for return of results in large-scale genomic sequencing projects.

Acceptability of Electronic Visits for Return of Research Results in the Mayo Clinic Biobank.

OBJECTIVE: To understand patient characteristics related to acceptability of returning individual research results via various modalities, focusing on electronic visits (e-visits). PATIENTS AND METHODS: Twelve hundred participants from the Mayo Clinic Biobank were selected using a stratified random sampling approach based on sex, age, and education level. Mailed surveys ascertained return of results preferences for 2 disease vignettes (cystic fibrosis and hereditary breast cancer) and a pharmacogenomics vignette. The study was conducted from October 1, 2013, through March 31, 2014. RESULTS: In all, 685 patients (57%) responded, and 60% reported liking e-visits, although the option of receiving results in an office visit was liked most frequently. Multivariable logistic models showed that the odds of liking the use of e-visits for returning results for cystic fibrosis and hereditary breast cancer were higher among those with higher education and better genetic knowledge and among those not living in proximity to the Mayo Clinic (Rochester, Minnesota). Level of genetic knowledge was not considerably associated with accepting e-visits, whereas education level remained important. For all vignettes, those who are divorced were less likely to accept e-visits. CONCLUSION: Researchers are faced with a difficult challenge of returning results with a method that is both acceptable to recipients and logistically feasible. This study implies that the use of e-visits may be a viable option for return of results to stratify the chasm between in-person genetic counseling and online portal receipt of results.

The Return of Actionable Variants Empirical (RAVE) Study, a Mayo Clinic Genomic Medicine Implementation Study: Design and Initial Results.

OBJECTIVES: To identify clinically actionable genetic variants from targeted sequencing of 68 disease-related genes, estimate their penetrance, and assess the impact of disclosing results to participants and providers. PATIENTS AND METHODS: The Return of Actionable Variants Empirical (RAVE) Study investigates outcomes following the return of pathogenic/likely pathogenic (P/LP) variants in 68 disease-related genes. The study was initiated in December 2016 and is ongoing. Targeted sequencing was performed in 2533 individuals with hyperlipidemia or colon polyps. The electronic health records (EHRs) of participants carrying P/LP variants in 36 cardiovascular disease (CVD) genes were manually reviewed to ascertain the presence of relevant traits. Clinical outcomes, health care utilization, family communication, and ethical and psychosocial implications of disclosure of genomic results are being assessed by surveys, telephone interviews, and EHR review. RESULTS: Of 29,208 variants in the 68 genes, 1915 were rare (frequency <1%) and putatively functional, and 102 of these (60 in 36 CVD genes) were labeled P/LP based on the American College of Medical Genetics and Genomics framework. Manual review of the EHRs of participants (n=73 with P/LP variants in CVD genes) revealed that 33 had the expected trait(s); however, only 6 of 45 participants with non-familial hypercholesterolemia (FH) P/LP variants had the expected traits. CONCLUSION: Expected traits were present in 13% of participants with P/LP variants in non-FH CVD genes, suggesting low penetrance; this estimate may change with additional testing performed as part of the clinical evaluation. Ongoing analyses of the RAVE Study will inform best practices for genomic medicine.

Ethical Considerations Related to Return of Results from Genomic Medicine Projects: The eMERGE Network (Phase III) Experience.

We examined the Institutional Review Board (IRB) process at 9 academic institutions in the electronic Medical Records and Genomics (eMERGE) Network, for proposed electronic health record-based genomic medicine studies, to identify common questions and concerns. Sequencing of 109 disease related genes and genotyping of 14 actionable variants is being performed in ~28,100 participants from the 9 sites. Pathogenic/likely pathogenic variants in actionable genes are being returned to study participants. We examined each site's research protocols, informed-consent materials, and interactions with IRB staff. Research staff at each site completed questionnaires regarding their IRB interactions. The time to prepare protocols for IRB submission, number of revisions and time to approval ranged from 10-261 days, 0-11, and 11-90 days, respectively. IRB recommendations related to the readability of informed consent materials, specifying the full range of potential risks, providing options for receiving limited results or withdrawal, sharing of information with family members, and establishing the mechanisms to answer participant questions. IRBs reviewing studies that involve the return of results from genomic sequencing have a diverse array of concerns, and anticipating these concerns can help investigators to more effectively engage IRBs.

Variability in assigning pathogenicity to incidental findings: insights from LDLR sequence linked to the electronic health record in 1013 individuals.

Knowledge of variant pathogenicity is key to implementing genomic medicine. We describe variability between expert reviewers in assigning pathogenicity to sequence variants in LDLR, the causal gene in the majority of cases of familial hypercholesterolemia. LDLR was sequenced on the Illumina HiSeq platform (average read depth >200 × ) in 1013 Mayo Biobank participants recruited from 2012 to 2013. Variants with a minor allele frequency (MAF) <5% predicted to be functional or referenced in HGMD (Human Gene Mutation Database) or NCBI-ClinVar databases were reviewed. To assign pathogenicity, variant frequency in population data sets, computational predictions, reported observations and patient-level data including electronic health record-based post hoc phenotyping were leveraged. Of 178 LDLR variants passing quality control, 25 were selected for independent review using either an in-house protocol or a disease/gene-specific semi-quantitative framework based on the American College of Medical Genetics and Genomics-recommended lines of evidence. NCBI-ClinVar included interpretations for all queried variants with 74% (14/19) of variants with >1 submitter showing inconsistency in classification and 26% (5/19) appearing with conflicting clinical actionability. The discordance rate (one-step level of disagreement out of five classes in variant interpretation) between the reviewers was 40% (10/25). Two LDLR variants were independently deemed clinically actionable and returnable. Interpretation of LDLR variants was often discordant among ClinVar submitters and between expert reviewers. A quantitative approach based on strength of each predefined criterion in the context of specific genes and phenotypes may yield greater consistency between different reviewers.

The Sangre Por Salud Biobank: Facilitating Genetic Research in an Underrepresented Latino Community.

BACKGROUND/AIMS: The Sangre Por Salud (Blood for Health; SPS) Biobank was created for the purpose of expanding precision medicine research to include underrepresented Latino patients. It is the result of a unique collaboration between Mayo Clinic and Mountain Park Health Center, a federally qualified community health center in Phoenix, Arizona. This report describes the rationale, development, implementation, and characteristics of the SPS Biobank. METHODS: Latino adults (ages 18-85 years) who were active patients within Mountain Park Health Center's internal medicine practice in Phoenix, Ariz., and had no history of diabetes were eligible. Participants provided a personal and family history of chronic disease, completed a sociodemographic, psychosocial, and behavioral questionnaire, underwent a comprehensive cardiometabolic risk assessment (anthropometrics, blood pressure and labs), and provided blood samples for banking. Laboratory results of cardiometabolic testing were returned to the participants and their providers through the electronic health record. RESULTS: During the first 2 years of recruitment into the SPS Biobank, 2,335 patients were approached and 1,432 (61.3%) consented to participate; 1,354 (94.5%) ultimately completed all requisite questionnaires and medical evaluations. The cohort is primarily Spanish-speaking (72.9%), female (73.3%), with a mean age of 41.3 ± 12.5 years. Most participants were born outside of the US (77.9%) and do not have health insurance (77.5%). The prevalence of overweight (35.5%) and obesity (45.0%) was high, as was previously unidentified prediabetes (55.9%), type 2 diabetes (7.4%), prehypertension (46.8%), and hypertension (16.2%). The majority of participants rated their health as good to excellent (72.1%) and, as a whole, described their overall quality of life as high (7.9/10). CONCLUSION: Collaborative efforts such as the SPS Biobank are critical for ensuring that underrepresented minority populations are included in precision medicine initiatives and biomedical research that seeks to improve human health and reduce the burdens of disease.

Health behaviors and quality of life predictors for risk of hospitalization in an electronic health record-linked biobank.

BACKGROUND: Hospital risk stratification models using electronic health records (EHRs) often use age and comorbid health burden. Our primary aim was to determine if quality of life or health behaviors captured in an EHR-linked biobank can predict future risk of hospitalization. METHODS: Participants in the Mayo Clinic Biobank completed self-administered questionnaires at enrollment that included quality of life and health behaviors. Participants enrolled as of December 31, 2010 were followed for one year to ascertain hospitalization. Data on comorbidities and hospitalization were derived from the Mayo Clinic EHR. Hazard ratios (HR) and 95% confidence interval (CI) were used, adjusted for age and sex. We used gradient boosting machines models to integrate multiple factors. Different models were compared using C-statistic. RESULTS: Of the 8,927 eligible Mayo Clinic Biobank participants, 834 (9.3%) were hospitalized. Self-perceived health status and alcohol use had the strongest associations with risk of hospitalization. Compared to participants with excellent self-perceived health, those reporting poor/fair health had higher risk of hospitalization (HR =3.66, 95% CI 2.74-4.88). Alcohol use was inversely associated with hospitalization (HR =0.57 95% CI 0.45-0.72). The gradient boosting machines model estimated self-perceived health as the most influential factor (relative influence =16%). The predictive ability of the model based on comorbidities was slightly higher than the one based on the self-perceived health (C-statistic =0.67 vs 0.65). CONCLUSION: This study demonstrates that self-perceived health may be an important piece of information to add to the EHR. It may be another method to determine hospitalization risk.