Low antibody levels associated with significantly increased rate of SARS-CoV-2 infection in a highly vaccinated population from the US National Basketball Association.

SARS-CoV-2 antibody levels may serve as a correlate for immunity and could inform optimal booster timing. The relationship between antibody levels and protection from infection was evaluated in vaccinated individuals from the US National Basketball Association who had antibody levels measured at a single time point from September 12, 2021, to December 31, 2021. Cox proportional hazards models were used to estimate the risk of infection within 90 days of serologic testing by antibody level (<250, 250-800, and >800 AU/mL1 ), adjusting for age, time since last vaccine dose, and history of SARS-CoV-2 infection. Individuals were censored on date of booster receipt. The analytic cohort comprised 2323 individuals and was 78.2% male, 68.1% aged ≤40 years, and 56.4% vaccinated (primary series) with the Pfizer-BioNTech mRNA vaccine. Among the 2248 (96.8%) individuals not yet boosted at antibody testing, 77% completed their primary vaccine series 4-6 months before testing and the median (interquartile range) antibody level was 293.5 (interquartile range: 121.0-740.5) AU/mL. Those with levels <250 AU/mL (adj hazard ratio [HR]: 2.4; 95% confidence interval [CI]: 1.5-3.7) and 250-800 AU/mL (adj HR: 1.5; 95% CI: 0.98-2.4) had greater infection risk compared to those with levels >800 AU/mL. Antibody levels could inform individual COVID-19 risk and booster scheduling.

The "Bubble": What Can Be Learned from the National Basketball Association (NBA)'s 2019-20 Season Restart in Orlando during the COVID-19 Pandemic.

BACKGROUND: The National Basketball Association (NBA) suspended operations in response to the COVID-19 pandemic in March 2020. To safely complete the 2019-20 season, the NBA created a closed campus in Orlando, Florida, known as the NBA "Bubble." More than 5000 individuals lived, worked, and played basketball at a time of high local prevalence of SARS-CoV-2. METHODS: Stringent protocols governed campus life to protect NBA and support personnel from contracting COVID-19. Participants quarantined before departure and upon arrival. Medical and social protocols required that participants remain on campus, test regularly, physically distance, mask, use hand hygiene, and more. Cleaning, disinfection, and air filtration was enhanced. Campus residents were screened daily and confirmed cases of COVID-19 were investigated. RESULTS: In the Bubble population, 148 043 COVID-19 reverse transcriptase PCR (RT-PCR) tests were performed across approximately 5000 individuals; Orlando had a 4% to 15% test positivity rate in this timeframe. There were 44 COVID-19 cases diagnosed either among persons during arrival quarantine or in non-team personnel while working on campus after testing but before receipt of a positive result. No cases of COVID-19 were identified among NBA players or NBA team staff living in the Bubble once cleared from quarantine. CONCLUSIONS: Drivers of success included the requirement for players and team staff to reside and remain on campus, well-trained compliance monitors, unified communication, layers of protection between teams and the outside, activation of high-quality laboratory diagnostics, and available mental health services. An emphasis on data management, evidence-based decision-making, and the willingness to evolve protocols were instrumental to successful operations. These lessons hold broad applicability for future pandemic preparedness efforts.

Viral kinetics of sequential SARS-CoV-2 infections.

The impact of a prior SARS-CoV-2 infection on the progression of subsequent infections has been unclear. Using a convenience sample of 94,812 longitudinal RT-qPCR measurements from anterior nares and oropharyngeal swabs, we identified 71 individuals with two well-sampled SARS-CoV-2 infections between March 11th, 2020, and July 28th, 2022. We compared the SARS-CoV-2 viral kinetics of first vs. second infections in this group, adjusting for viral variant, vaccination status, and age. Relative to first infections, second infections usually featured a faster clearance time. Furthermore, a person's relative (rank-order) viral clearance time, compared to others infected with the same variant, was roughly conserved across first and second infections, so that individuals who had a relatively fast clearance time in their first infection also tended to have a relatively fast clearance time in their second infection (Spearman correlation coefficient: 0.30, 95% credible interval (0.12, 0.46)). These findings provide evidence that, like vaccination, immunity from a prior SARS-CoV-2 infection shortens the duration of subsequent acute SARS-CoV-2 infections principally by reducing viral clearance time. Additionally, there appears to be an inherent element of the immune response, or some other host factor, that shapes a person's relative ability to clear SARS-CoV-2 infection that persists across sequential infections.

Quantifying the impact of immune history and variant on SARS-CoV-2 viral kinetics and infection rebound: A retrospective cohort study.

Background: The combined impact of immunity and SARS-CoV-2 variants on viral kinetics during infections has been unclear. Methods: We characterized 1,280 infections from the National Basketball Association occupational health cohort identified between June 2020 and January 2022 using serial RT-qPCR testing. Logistic regression and semi-mechanistic viral RNA kinetics models were used to quantify the effect of age, variant, symptom status, infection history, vaccination status and antibody titer to the founder SARS-CoV-2 strain on the duration of potential infectiousness and overall viral kinetics. The frequency of viral rebounds was quantified under multiple cycle threshold (Ct) value-based definitions. Results: Among individuals detected partway through their infection, 51.0% (95% credible interval [CrI]: 48.3-53.6%) remained potentially infectious (Ct <30) 5 days post detection, with small differences across variants and vaccination status. Only seven viral rebounds (0.7%; N=999) were observed, with rebound defined as 3+days with Ct <30 following an initial clearance of 3+days with Ct ≥30. High antibody titers against the founder SARS-CoV-2 strain predicted lower peak viral loads and shorter durations of infection. Among Omicron BA.1 infections, boosted individuals had lower pre-booster antibody titers and longer clearance times than non-boosted individuals. Conclusions: SARS-CoV-2 viral kinetics are partly determined by immunity and variant but dominated by individual-level variation. Since booster vaccination protects against infection, longer clearance times for BA.1-infected, boosted individuals may reflect a less effective immune response, more common in older individuals, that increases infection risk and reduces viral RNA clearance rate. The shifting landscape of viral kinetics underscores the need for continued monitoring to optimize isolation policies and to contextualize the health impacts of therapeutics and vaccines. Funding: Supported in part by CDC contract #200-2016-91779, a sponsored research agreement to Yale University from the National Basketball Association contract #21-003529, and the National Basketball Players Association.

SARS-CoV-2 Transmission Risk Among National Basketball Association Players, Staff, and Vendors Exposed to Individuals With Positive Test Results After COVID-19 Recovery During the 2020 Regular and Postseason.

Importance: Clinical data are lacking regarding the risk of viral transmission from individuals who have positive reverse-transcription-polymerase chain reaction (RT-PCR) SARS-CoV-2 test results after recovery from COVID-19. Objective: To describe case characteristics, including viral dynamics and transmission of infection, for individuals who have clinically recovered from SARS-CoV-2 infection but continued to have positive test results following discontinuation of isolation precautions. Design, Setting, and Participants: This retrospective cohort study used data collected from June 11, 2020, to October 19, 2020, as part of the National Basketball Association (NBA) closed campus occupational health program in Orlando, Florida, which required daily RT-PCR testing and ad hoc serological testing for SARS-CoV-2 IgG antibodies. Nearly 4000 NBA players, staff, and vendors participated in the NBA's regular and postseason occupational health program in Orlando. Persistent positive cases were those who recovered from a documented SARS-CoV-2 infection, satisfied US Centers for Disease Control and Prevention criteria for discontinuation of isolation precautions, and had at least 1 postinfection positive RT-PCR test(s) result. Exposures: Person-days of participation in indoor, unmasked activities that involved direct exposure between persistent positive cases and noninfected individuals. Main Outcomes and Measures: Transmission of SARS-CoV-2 following interaction with persistent positive individuals, as measured by the number of new COVID-19 cases in the Orlando campus program. Results: Among 3648 individuals who participated, 36 (1%) were persistent positive cases, most of whom were younger than 30 years (24 [67%]) and male (34 [94%]). Antibodies were detected in 33 individuals (91.7%); all remained asymptomatic following the index persistent positive RT-PCR result. Cycle threshold values for persistent positive RT-PCR test results were typically above the Roche cobas SARS-CoV-2 limit of detection. Cases were monitored for up to 100 days (mean [SD], 51 [23.9] days), during which there were at least 1480 person-days of direct exposure activities, with no transmission events or secondary infections of SARS-CoV-2 detected (0 new cases). Conclusions and Relevance: In this retrospective cohort study of the 2020 NBA closed campus occupational health program, recovered individuals who continued to test positive for SARS-CoV-2 following discontinuation of isolation were not infectious to others. These findings support time-based US Centers of Disease Control and Prevention recommendations for ending isolation.

Cross-cancer evaluation of polygenic risk scores for 16 cancer types in two large cohorts.

Even distinct cancer types share biological hallmarks. Here, we investigate polygenic risk score (PRS)-specific pleiotropy across 16 cancers in European ancestry individuals from the Genetic Epidemiology Research on Adult Health and Aging cohort (16,012 cases, 50,552 controls) and UK Biobank (48,969 cases, 359,802 controls). Within cohorts, each PRS is evaluated in multivariable logistic regression models against all other cancer types. Results are then meta-analyzed across cohorts. Ten positive and one inverse cross-cancer associations are found after multiple testing correction. Two pairs show bidirectional associations; the melanoma PRS is positively associated with oral cavity/pharyngeal cancer and vice versa, whereas the lung cancer PRS is positively associated with oral cavity/pharyngeal cancer, and the oral cavity/pharyngeal cancer PRS is inversely associated with lung cancer. Overall, we validate known, and uncover previously unreported, patterns of pleiotropy that have the potential to inform investigations of risk prediction, shared etiology, and precision cancer prevention strategies.

A Large-Scale Association Study Detects Novel Rare Variants, Risk Genes, Functional Elements, and Polygenic Architecture of Prostate Cancer Susceptibility.

To identify rare variants associated with prostate cancer susceptibility and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we conducted an integrated study of prostate cancer genetic etiology in two cohorts using custom genotyping microarrays, large imputation reference panels, and functional annotation approaches. Specifically, 11,984 men (6,196 prostate cancer cases and 5,788 controls) of European ancestry from Northern California Kaiser Permanente were genotyped and meta-analyzed with 196,269 men of European ancestry (7,917 prostate cancer cases and 188,352 controls) from the UK Biobank. Three novel loci, including two rare variants (European ancestry minor allele frequency < 0.01, at 3p21.31 and 8p12), were significant genome wide in a meta-analysis. Gene-based rare variant tests implicated a known prostate cancer gene (HOXB13), as well as a novel candidate gene (ILDR1), which encodes a receptor highly expressed in prostate tissue and is related to the B7/CD28 family of T-cell immune checkpoint markers. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants at HOXB13 and other loci, reflecting their evolutionary history. In addition, a polygenic risk score (PRS) of 188 prostate cancer variants was strongly associated with risk (90th vs. 40th-60th percentile OR = 2.62, P = 2.55 × 10-191). Many of the 188 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a 6-fold difference in log-probability of androgen receptor binding at the variant rs2680708 (17q22). Rare variant and PRS associations, with concomitant functional interpretation of risk mechanisms, can help clarify the full genetic architecture of prostate cancer and other complex traits. SIGNIFICANCE: This study maps the biological relationships between diverse risk factors for prostate cancer, integrating different functional datasets to interpret and model genome-wide data from over 200,000 men with and without prostate cancer.See related commentary by Lachance, p. 1637.

Multiple Stakeholder Views on Data Sharing in a Biobank in an Integrated Healthcare Delivery System: Implications for Biobank Governance.

BACKGROUND: Beginning in 2005, researchers at Kaiser Permanente Northern California (KPNC) Division of Research developed the Research Program on Genes, Environment, and Health (RPGEH), a research resource of linked biospecimens, health surveys, and electronic health records on more than 200,000 adult KPNC members. This study examined multiple stakeholders' values and preferences regarding protection of participants' privacy and wide sharing of participant data by RPGEH. METHODS: We conducted 45 semi-structured interviews in person or via phone and two focus groups with seven stakeholder groups, including RPGEH participants and decliners who are KPNC members, KPNC research scientists, external scientists, leadership, Human Subjects Research Protection Program staff, and RPGEH Community Advisory Panel members. RESULTS: Three major themes emerged related to: (1) perceived individual and social harms associated with data sharing; (2) concerns to address when governing access to RPGEH data; and (3) impact of a blurred boundary between research and clinical care in the context of biobanking. CONCLUSIONS: The study results were considered in the development of RPGEH data governance and motivated the inclusion of KPNC Community Advisory Panel members and ELSI experts on committees that evaluate data access proposals. Our findings can help inform other biobanks going through similar processes developing data sharing and access policies.

Update on the State of the Science for Analytical Methods for Gene-Environment Interactions.

The analysis of gene-environment interaction (G×E) may hold the key for further understanding the etiology of many complex traits. The current availability of high-volume genetic data, the wide range in types of environmental data that can be measured, and the formation of consortiums of multiple studies provide new opportunities to identify G×E but also new analytical challenges. In this article, we summarize several statistical approaches that can be used to test for G×E in a genome-wide association study. These include traditional models of G×E in a case-control or quantitative trait study as well as alternative approaches that can provide substantially greater power. The latest methods for analyzing G×E with gene sets and with data in a consortium setting are summarized, as are issues that arise due to the complexity of environmental data. We provide some speculation on why detecting G×E in a genome-wide association study has thus far been difficult. We conclude with a description of software programs that can be used to implement most of the methods described in the paper.

The Population Burden of Cancer: Research Driven by the Catchment Area of a Cancer Center.

Cancer centers, particularly those supported by the National Cancer Institute, are charged with reducing the cancer burden in their catchment area. However, methods to define both the catchment area and the cancer burden are diverse and range in complexity often based on data availability, staff resources, or confusion about what is required. This article presents a review of the current literature identifying 4 studies that have defined various aspects of the cancer burden in a defined geographical area and highlights examples of how some cancer centers and other health institutions have defined their catchment area and characterized the cancer burden within it. We then present a detailed case study of an approach applied by the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center to define its catchment area and its population cancer burden. We cite examples of how the Cancer Center research portfolio addresses the defined cancer burden. Our case study outlines a systematic approach to using publicly available data, such as cancer registry data, that are accessible by all cancer centers. By identifying gaps and formulating future research directions based on the needs of the population within the catchment area, epidemiologic studies and other types of cancer research can be directed to the population served. This review can help guide cancer centers in developing an approach to defining their own catchment area as mandated and applying research findings to this defined population.

Cis-eQTL-based trans-ethnic meta-analysis reveals novel genes associated with breast cancer risk.

Breast cancer is the most common solid organ malignancy and the most frequent cause of cancer death among women worldwide. Previous research has yielded insights into its genetic etiology, but there remains a gap in the understanding of genetic factors that contribute to risk, and particularly in the biological mechanisms by which genetic variation modulates risk. The National Cancer Institute's "Up for a Challenge" (U4C) competition provided an opportunity to further elucidate the genetic basis of the disease. Our group leveraged the seven datasets made available by the U4C organizers and data from the publicly available UK Biobank cohort to examine associations between imputed gene expression and breast cancer risk. In particular, we used reference datasets describing the breast tissue and whole blood transcriptomes to impute expression levels in breast cancer cases and controls. In trans-ethnic meta-analyses of U4C and UK Biobank data, we found significant associations between breast cancer risk and the expression of RCCD1 (joint p-value: 3.6x10-06) and DHODH (p-value: 7.1x10-06) in breast tissue, as well as a suggestive association for ANKLE1 (p-value: 9.3x10-05). Expression of RCCD1 in whole blood was also suggestively associated with disease risk (p-value: 1.2x10-05), as were expression of ACAP1 (p-value: 1.9x10-05) and LRRC25 (p-value: 5.2x10-05). While genome-wide association studies (GWAS) have implicated RCCD1 and ANKLE1 in breast cancer risk, they have not identified the remaining three genes. Among the genetic variants that contributed to the predicted expression of the five genes, we found 23 nominally (p-value < 0.05) associated with breast cancer risk, among which 15 are not in high linkage disequilibrium with risk variants previously identified by GWAS. In summary, we used a transcriptome-based approach to investigate the genetic underpinnings of breast carcinogenesis. This approach provided an avenue for deciphering the functional relevance of genes and genetic variants involved in breast cancer.

Detecting gene-environment interactions in human birth defects: Study designs and statistical methods.

BACKGROUND: The National Birth Defects Prevention Study (NBDPS) contains a wealth of information on affected and unaffected family triads, and thus provides numerous opportunities to study gene-environment interactions (G×E) in the etiology of birth defect outcomes. Depending on the research objective, several analytic options exist to estimate G×E effects that use varying combinations of individuals drawn from available triads. METHODS: In this study, we discuss important considerations in the collection of genetic data and environmental exposures. RESULTS: We will also present several population- and family-based approaches that can be applied to data from the NBDPS including case-control, case-only, family-based trio, and maternal versus fetal effects. For each, we describe the data requirements, applicable statistical methods, advantages, and disadvantages. CONCLUSION: A range of approaches can be used to evaluate potentially important G×E effects in the NBDPS. Investigators should be aware of the limitations inherent to each approach when choosing a study design and interpreting results.

Leveraging state cancer registries to measure and improve the quality of cancer care: a potential strategy for California and beyond.

Despite recent increased attention to healthcare performance and the burden of disease from cancer, measures of quality of cancer care are not readily available. In 2013, the California HealthCare Foundation convened an expert workgroup to explore the potential for leveraging data in the California Cancer Registry (CCR), one of the world's largest population-based cancer registries, for measuring and improving the quality of cancer care. The workgroup assessed current registry operations, the value to be gained by linking CCR data with health insurance claims or encounter data and clinical data contained in health system electronic health records, and potential barriers to these linkages. The workgroup concluded that: 1) The CCR mandate should be expanded to include use of its data for quality of cancer care measurement and public reporting; and 2) a system should be developed to support linkage of registry data with both claims data and provider electronic health record data.

Video-based educational tool improves patient comprehension of common prostate health terminology.

BACKGROUND: Health care providers often counsel prostate cancer patients about treatment options with medical terminology. However, studies have demonstrated a severe lack of comprehension of these terms, particularly in underserved populations. It was hypothesized that a video-based educational tool would significantly improve the understanding of key terms related to prostate health in a predominantly lower literacy population. METHODS: A software application was developed by various experts, including urologists and human-computer interaction specialists, to serve as a video-based educational tool emphasizing narrated animations to promote understanding of terms related to urinary, bowel, and sexual function. This application was viewed by patients recruited from 2 low-income safety net clinics, where a previously developed survey was administered to assess pre- and postintervention levels of comprehension. RESULTS: Fifty-six patients with a mean literacy level of 7th to 8th grade completed the study. Patients achieved statistically significant improvements in comprehension for the majority of the terms after the video intervention, with notable improvements including the terms incontinence (from 14% to 50%), bowels (from 14% to 46%), and impotence (from 58% to 84%). Patients demonstrated significant gains in their understanding of the function of the prostate (from 11% to 30%) and in their ability to locate the prostate on anatomic drawings (from 50% to 82%). CONCLUSIONS: This video-based educational tool is an effective method for overcoming the severe lack of comprehension of prostate health terminology among patients. The improvements achieved have the potential to enhance patient participation in shared and informed decision making and to support combined visual-audio multimedia as a promising tool for prostate cancer education.

External validation of the modified Glasgow prognostic score for renal cancer.

PURPOSE: The modified Glasgow prognostic Score (mGPS) incorporates C-reactive protein and albumin as a clinically useful marker of tumor behavior. The ability of the mGPS to predict metastasis in localized renal cell carcinoma (RCC) remains unknown in an external validation cohort. PATIENTS AND METHODS: Patients with clinically localized clear cell RCC were followed for 1 year post-operatively. Metastases were identified radiologically. Patients were categorized by mGPS score as low-risk (mGPS = 0 points), intermediate-risk (mGPS = 1 point) and high-risk (mGPS = 2 points). Univariate, Kaplan-Meier and multivariate Cox regression analyses examined Recurrence -free survival (RFS) across patient and disease characteristics. RESULTS: Of the 129 patients in this study, 23.3% developed metastases. Of low, intermediate and high risk patients, 10.1%, 38.9% and 89.9% recurred during the study. After accounting for various patient and tumor characteristics in multivariate analysis including stage and grade, only mGPS was significantly associated with RFS. Compared with low-risk patients, intermediate- and high-risk patients experienced a 4-fold (hazard ratios [HR]: 4.035, 95% confidence interval [CI]: 1.312-12.415, P = 0.015) and 7-fold (HR: 7.012, 95% CI: 2.126-23.123 P < 0.001) risk of metastasis, respectively. CONCLUSIONS: mGPS is a robust predictor of metastasis following potentially curative nephrectomy for localized RCC. Clinicians may consider mGPS as an adjunct to identify high-risk patients for possible enrollment into clinical trials or for patient counseling.

Severe lack of comprehension of common prostate health terms among low-income inner-city men.

BACKGROUND: Patients diagnosed with prostate cancer are often counseled about treatment options with the use of terms that are part of the "core vocabulary" of prostate cancer. It is hypothesized that predominantly lower literacy patients would demonstrate a severe lack of comprehension of prostate cancer terms, thus validating the findings of a previous single-institution study. METHODS: A previously developed survey was used to evaluate understanding of terms related to urinary, bowel, and sexual function. The survey was administered by trained evaluators at 2 safety net clinics that provide care for low-income, predominantly African American patients. Comprehension was assessed using semiqualitative methods coded by 2 independent investigators. Literacy and numeracy were also evaluated. RESULTS: Among 109 patients who completed the study, only 5% understood the function of the prostate, and 15%, 29%, and 32% understood the terms "incontinence," "urinary function," and "bowel habits," respectively. Lower levels of comprehension were observed for compound words, such as "vaginal intercourse" (58%), versus single words such as "intercourse" (95%), validating previous work. Median school level was 13 years, yet median literacy level was only ninth grade, and reading level was significantly correlated with comprehension. Only 30% of patients correctly calculated both a fraction and a percent. CONCLUSIONS: Lack of comprehension of prostate health terminology is pronounced in this patient population and may be widespread. This lack of comprehension potentially limits the ability of patients to participate in informed decision-making. These results validate the findings of previous studies and supports a continued need for refined methods of prostate cancer education.