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Importance: Most patients with pathogenic or likely pathogenic (P/LP) variants for breast cancer have not undergone genetic testing., Objective: To identify patients meeting family history criteria for genetic testing in the electronic health record (EHR)., Design, Setting, and Participants: This study included both cross-sectional (observation date, February 1, 2024) and retrospective cohort (observation period, January 1, 2018, to February 1, 2024) analyses. Participants included patients aged 18 to 79 years enrolled in Renown Health, a large health system in Northern Nevada. Genotype was known for 38 003 patients enrolled in Healthy Nevada Project (HNP), a population genomics study., Exposure: An EHR indicating that a patient is positive for criteria according to the Seven-Question Family History Questionnaire (hereafter, FHS7 positive) assessing familial risk for hereditary breast and ovarian cancer (HBOC)., Main Outcomes and Measures: The primary outcomes were the presence of P/LP variants in the ATM, BRCA1, BRCA2, CHEK2, or PALB2 genes (cross-sectional analysis) or a diagnosis of cancer (cohort analysis). Age-adjusted cancer incidence rates per 100 000 patients per year were calculated using the 2020 US population as the standard. Hazard ratios (HRs) for cancer attributable to FHS7-positive status were estimated using cause-specific hazard models., Results: Among 835 727 patients, 423 393 (50.7%) were female and 29 913 (3.6%) were FHS7 positive. Among those who were FHS7 positive, 24 535 (82.0%) had no evidence of prior genetic testing for HBOC in their EHR. Being FHS7 positive was associated with increased prevalence of P/LP variants in BRCA1/BRCA2 (odds ratio [OR], 3.34; 95% CI, 2.48-4.47), CHEK2 (OR, 1.62; 95% CI, 1.05-2.43), and PALB2 (OR, 2.84; 95% CI, 1.23-6.16) among HNP female individuals, and in BRCA1/BRCA2 (OR, 3.35; 95% CI, 1.93-5.56) among HNP male individuals. Being FHS7 positive was also associated with significantly increased risk of cancer among 131 622 non-HNP female individuals (HR, 1.44; 95% CI, 1.22-1.70) but not among 114 982 non-HNP male individuals (HR, 1.11; 95% CI, 0.87-1.42). Among 1527 HNP survey respondents, 352 of 383 EHR-FHS7 positive patients (91.9%) were survey-FHS7 positive, but only 352 of 883 survey-FHS7 positive patients (39.9%) were EHR-FHS7 positive. Of the 29 913 FHS7-positive patients, 19 764 (66.1%) were identified only after parsing free-text family history comments. Socioeconomic differences were also observed between EHR-FHS7-negative and EHR-FHS7-positive patients, suggesting disparities in recording family history., Conclusions and Relevance: In this cross-sectional study, EHR-derived FHS7 identified thousands of patients with familial risk for breast cancer, indicating a substantial gap in genetic testing. However, limitations in EHR family history data suggested that other identification methods, such as direct-to-patient questionnaires, are required to fully address this gap.

The clinical value of population-based genetic screening projects depends on the actions taken on the findings. The Healthy Nevada Project (HNP) is an all-comer genetic screening and research project based in northern Nevada. HNP participants with CDC Tier 1 findings of hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome (LS), or familial hypercholesterolemia (FH) are notified and provided with genetic counseling. However, the HNP subsequently takes a "hands-off" approach: it is the responsibility of notified participants to share their findings with their healthcare providers, and providers are expected to implement the recommended action plans. Thus, the HNP presents an opportunity to evaluate the efficiency of participant and provider responses to notification of important genetic findings, using electronic health records (EHRs) at Renown Health (a large regional hospital in northern Nevada). Out of 520 HNP participants with findings, we identified 250 participants who were notified of their findings and who had an EHR. 107 of these participants responded to a survey, with 76 (71%) indicating that they had shared their findings with their healthcare providers. However, a sufficiently specific genetic diagnosis appeared in the EHRs and problem lists of only 22 and 10%, respectively, of participants without prior knowledge. Furthermore, review of participant EHRs provided evidence of possible relevant changes in clinical care for only a handful of participants. Up to 19% of participants would have benefited from earlier screening due to prior presentation of their condition. These results suggest that continuous support for both participants and their providers is necessary to maximize the benefit of population-based genetic screening. We recommend that genetic screening projects require participants' consent to directly document their genetic findings in their EHRs. Additionally, we recommend that they provide healthcare providers with ongoing training regarding documentation of findings and with clinical decision support regarding subsequent care., Competing Interests: Authors JL and AB were employed by Helix. Authors SD and JG were employed by Renown Health. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Elhanan, Kiser, Neveux, Dabe, Bolze, Metcalf, Lu and Grzymski.)

Background: Air pollution has been linked to increased susceptibility to SARS-CoV-2. Thus, it has been suggested that wildfire smoke events may exacerbate the COVID-19 pandemic., Objectives: Our goal was to examine whether wildfire smoke from the 2020 wildfires in the western United States was associated with an increased rate of SARS-CoV-2 infections in Reno, Nevada., Methods: We conducted a time-series analysis using generalized additive models to examine the relationship between the SARS-CoV-2 test positivity rate at a large regional hospital in Reno and ambient PM2.5 from 15 May to 20 Oct 2020., Results: We found that a 10 µg/m 3 increase in the 7-day average PM2.5 concentration was associated with a 6.3% relative increase in the SARS-CoV-2 test positivity rate, with a 95% confidence interval (CI) of 2.5 to 10.3%. This corresponded to an estimated 17.7% (CI: 14.4-20.1%) increase in the number of cases during the time period most affected by wildfire smoke, from 16 Aug to 10 Oct., Significance: Wildfire smoke may have greatly increased the number of COVID-19 cases in Reno. Thus, our results substantiate the role of air pollution in exacerbating the pandemic and can help guide the development of public preparedness policies in areas affected by wildfire smoke, as wildfires are likely to coincide with the COVID-19 pandemic in 2021., (© 2021. The Author(s).)

Acute effects of outdoor air pollution on asthma exacerbations may vary by asthma phenotype (allergic vs nonallergic). Associations of ambient PM 2.5 and ozone concentrations with acute asthma visits (office, urgent, emergency, and hospitalization) were investigated using electronic medical records. International Classification of Disease codes were used to identify asthmatics, and classify them based on the presence or absence of an allergic comorbidity in their medical records. Daily 24-h average PM 2.5 , 8-h maximum ozone, and mean temperature were obtained from a centralized monitor. Using a time-stratified case-crossover approach, pollutant concentrations were modeled using moving averages and distributed lag nonlinear models (lag 0-6) to examine lag associations and nonlinear concentration-response. The adjusted odds ratios for a 10 µg/m 3 increase in 3-day moving average (lag 0-2) PM 2.5 in the two-pollutant models among patients with and without allergic comorbidities were 1.10 (95% confidence interval [CI]: 1.07, 1.13) and 1.05 (95% CI: 1.02, 1.09), respectively; and for a 20 ppb increase in 3-day moving average (lag 0-2) ozone were 1.08 (95% CI: 1.02, 1.14) and 1.00 (95% CI: 0.95, 1.05), respectively. Estimated odds ratios among patients with allergic comorbidities were consistently higher across age, sex, and temperature categories. Asthmatics with an allergic comorbidity may be more susceptible to ambient PM 2.5 and ozone.

Background: Health risks due to particulate matter (PM) from wildfires may differ from risk due to PM from other sources. In places frequently subjected to wildfire smoke, such as Reno, Nevada, it is critical to determine whether wildfire PM poses unique risks. Our goal was to quantify the difference in the association of adverse asthma events with PM on days when wildfire smoke was present versus days when wildfire smoke was not present., Methods: We obtained counts of visits for asthma at emergency departments and urgent care centers from a large regional healthcare system in Reno for the years 2013-2018. We also obtained dates when wildfire smoke was present from the Washoe County Health District Air Quality Management Division. We then examined whether the presence of wildfire smoke modified the association of PM 2.5 , PM 10-2.5 , and PM 10 with asthma visits using generalized additive models. We improved on previous studies by excluding wildfire-smoke days where the PM concentration exceeded the maximum PM concentration on other days, thus accounting for possible nonlinearity in the association between PM concentration and asthma visits., Results: Air quality was affected by wildfire smoke on 188 days between 2013 and 2018. We found that the presence of wildfire smoke increased the association of a 5 μg/m 3 increase in daily and three-day averages of PM 2.5 with asthma visits by 6.1% (95% confidence interval (CI): 2.1-10.3%) and 6.8% (CI: 1.2-12.7%), respectively. Similarly, the presence of wildfire smoke increased the association of a 5 μg/m 3 increase in daily and three-day averages of PM 10 with asthma visits by 5.5% (CI: 2.5-8.6%) and 7.2% (CI: 2.6-12.0%), respectively. We did not observe any significant increases in association for PM 10-2.5 or for seven-day averages of PM 2.5 and PM 10 ., Conclusions: Since we found significantly stronger associations of PM 2.5 and PM 10 with asthma visits when wildfire smoke was present, our results suggest that wildfire PM is more hazardous than non-wildfire PM for patients with asthma.

Three inherited autosomal dominant conditions-BRCA-related hereditary breast and ovarian cancer (HBOC), Lynch syndrome (LS) and familial hypercholesterolemia (FH)-have been termed the Centers for Disease Control and Prevention Tier 1 (CDCT1) genetic conditions, for which early identification and intervention have a meaningful potential for clinical actionability and a positive impact on public health 1 . In typical medical practice, genetic testing for these conditions is based on personal or family history, ethnic background or other demographic characteristics 2 . In this study of a cohort of 26,906 participants in the Healthy Nevada Project (HNP), we first evaluated whether population screening could efficiently identify carriers of these genetic conditions and, second, we evaluated the impact of genetic risk on health outcomes for these participants. We found a 1.33% combined carrier rate for pathogenic and likely pathogenic (P/LP) genetic variants for HBOC, LS and FH. Of these carriers, 21.9% of participants had clinically relevant disease, among whom 70% had been diagnosed with relevant disease before age 65. Moreover, 90% of the risk carriers had not been previously identified, and less than 19.8% of these had documentation in their medical records of inherited genetic disease risk, including family history. In a direct follow-up survey with all carriers, only 25.2% of individuals reported a family history of relevant disease. Our experience with the HNP suggests that genetic screening in patients could identify at-risk carriers, who would not be otherwise identified in routine care.

The aggregation of Electronic Health Records (EHR) and personalized genetics leads to powerful discoveries relevant to population health. Here we perform genome-wide association studies (GWAS) and accompanying phenome-wide association studies (PheWAS) to validate phenotype-genotype associations of BMI, and to a greater extent, severe Class 2 obesity, using comprehensive diagnostic and clinical data from the EHR database of our cohort. Three GWASs of 500,000 variants on the Illumina platform of 6,645 Healthy Nevada participants identified several published and novel variants that affect BMI and obesity. Each GWAS was followed with two independent PheWASs to examine associations between extensive phenotypes (incidence of diagnoses, condition, or disease), significant SNPs, BMI, and incidence of extreme obesity. The first GWAS examines associations with BMI in a cohort with no type 2 diabetics, focusing exclusively on BMI. The second GWAS examines associations with BMI in a cohort that includes type 2 diabetics. In the second GWAS, type 2 diabetes is a comorbidity, and thus becomes a covariate in the statistical model. The intersection of significant variants of these two studies is surprising. The third GWAS is a case vs. control study, with cases defined as extremely obese (Class 2 or 3 obesity), and controls defined as participants with BMI between 18.5 and 25. This last GWAS identifies strong associations with extreme obesity, including established variants in the FTO and NEGR1 genes, as well as loci not yet linked to obesity. The PheWASs validate published associations between BMI and extreme obesity and incidence of specific diagnoses and conditions, yet also highlight novel links. This study emphasizes the importance of our extensive longitudinal EHR database to validate known associations and identify putative novel links with BMI and obesity., (Copyright © 2020 Schlauch et al.)

Understanding the impact of rare variants is essential to understanding human health. We analyze rare (MAF < 0.1%) variants against 4264 phenotypes in 49,960 exome-sequenced individuals from the UK Biobank and 1934 phenotypes (1821 overlapping with UK Biobank) in 21,866 members of the Healthy Nevada Project (HNP) cohort who underwent Exome + sequencing at Helix. After using our rare-variant-tailored methodology to reduce test statistic inflation, we identify 64 statistically significant gene-based associations in our meta-analysis of the two cohorts and 37 for phenotypes available in only one cohort. Singletons make significant contributions to our results, and the vast majority of the associations could not have been identified with a genotyping chip. Our results are available for interactive browsing in a webapp (https://ukb.research.helix.com). This comprehensive analysis illustrates the biological value of large, deeply phenotyped cohorts of unselected populations coupled with NGS data.

In this study, we perform a full genome-wide association study (GWAS) to identify statistically significantly associated single nucleotide polymorphisms (SNPs) with three red blood cell (RBC) components and follow it with two independent PheWASs to examine associations between phenotypic data (case-control status of diagnoses or disease), significant SNPs, and RBC component levels. We first identified associations between the three RBC components: mean platelet volume (MPV), mean corpuscular volume (MCV), and platelet counts (PC), and the genotypes of approximately 500,000 SNPs on the Illumina Infimum DNA Human OmniExpress-24 BeadChip using a single cohort of 4,673 Northern Nevadans. Twenty-one SNPs in five major genomic regions were found to be statistically significantly associated with MPV, two regions with MCV, and one region with PC, with p<5x10-8. Twenty-nine SNPs and nine chromosomal regions were identified in 30 previous GWASs, with effect sizes of similar magnitude and direction as found in our cohort. The two strongest associations were SNP rs1354034 with MPV (p = 2.4x10-13) and rs855791 with MCV (p = 5.2x10-12). We then examined possible associations between these significant SNPs and incidence of 1,488 phenotype groups mapped from International Classification of Disease version 9 and 10 (ICD9 and ICD10) codes collected in the extensive electronic health record (EHR) database associated with Healthy Nevada Project consented participants. Further leveraging data collected in the EHR, we performed an additional PheWAS to identify associations between continuous red blood cell (RBC) component measures and incidence of specific diagnoses. The first PheWAS illuminated whether SNPs associated with RBC components in our cohort were linked with other hematologic phenotypic diagnoses or diagnoses of other nature. Although no SNPs from our GWAS were identified as strongly associated to other phenotypic components, a number of associations were identified with p-values ranging between 1x10-3 and 1x10-4 with traits such as respiratory failure, sleep disorders, hypoglycemia, hyperglyceridemia, GERD and IBS. The second PheWAS examined possible phenotypic predictors of abnormal RBC component measures: a number of hematologic phenotypes such as thrombocytopenia, anemias, hemoglobinopathies and pancytopenia were found to be strongly associated to RBC component measures; additional phenotypes such as (morbid) obesity, malaise and fatigue, alcoholism, and cirrhosis were also identified to be possible predictors of RBC component measures., Competing Interests: This commercial affiliation [23andMe] does not alter our adherence to PLOS ONE policies on sharing data and materials.

We observe a net beam excess of 8.7+/-6.3(stat)+/-2.4(syst) events, above 160 MeV, resulting from the charged-current reaction of nu(micro) and/or nu;(mu) on C and H in the LSND detector. No beam-related muon background is expected in this energy regime. Within an analysis framework of pi(0)-->nu(mu)nu;(mu), we set a direct upper limit for this branching ratio of Gamma(pi(0)-->nu(mu)nu;(mu))/Gamma(pi(0)-->all)<1.6 x 10(-6) at 90% confidence level.