BackgroundEmergency department (ED) visit volumes can be especially high during the Christmas–New Year holidays, a period occurring during the influenza season in Canada.MethodsUsing daily data, we examined the relationship between ED visits for the chief complaint “cough” (for Edmonton, Alberta residents) and laboratory detections for influenza A and respiratory syncytial virus (RSV) (for Edmonton and surrounding areas), lagged 0–5 days ahead, for non‐pandemic years (2004–2008 and 2010–2014) using multivariable linear regression adjusting for temporal variables. We defined these cough‐related visits as influenza‐like illness (ILI)‐related ED visits and, for 2004–2014, compared Christmas–New Year holiday (December 24–January 3) and non‐holiday volumes during the influenza season (October–April).ResultsAdjusting for temporal variables, ILI‐related ED visits were significantly associated with laboratory detections for influenza A and RSV. During non‐pandemic years, the highest peak in ILI‐related visit volumes always occurred during the holidays. The median number of holiday ILI‐related visits/day (42.5) was almost twice the non‐holiday median (24) and was even higher in 2012–2013 (80) and 2013–2014 (86). Holiday ILI‐related ED visit volumes/100 000 population ranged from 56.0 (2010–2011) to 117.4 (2012–2013). In contrast, lower visit volumes occurred during the holidays of pandemic‐affected years (2008–2010).ConclusionsDuring non‐pandemic years, ILI‐related ED visit volumes were associated with variations in detections for influenza A and RSV and always peaked during the Christmas–New Year holidays. This predictability should be used to prepare for, and possibly prevent, this increase in healthcare use; however, interventions beyond disease prevention strategies are likely needed.
Numerous common genetic variants have been linked to breast cancer (BCa) risk, but they only partially explain the total BCa heritability. Inference from Nordic population-based twin data indicates rare high-risk loci as the chief determinant of BCa risk. Here, we use haplotypes, rather than single variants, to identify rare high-risk loci for BCa. With computationally-phased genotypes from 181,034 white British women in the UK Biobank, a genome-wide haplotype-BCa association analysis was conducted using sliding windows of 5-500 consecutive array-genotyped variants. In the discovery stage, haplotype-BCa associations were evaluated retrospectively in the pre-study-enrollment data including 5,487 BCa cases. BCa hazard ratios (HRs) for additive haplotypic effects were estimated using Cox regression. The replication analysis included a prospective cohort of women free of BCa at enrollment, of whom 3,524 later developed BCa. This two-stage analysis detected 13 rare loci (frequency <1%), each associated with an appreciable BCa-risk increase (discovery: HRs=2.84-6.10, P-value<5x10-8; replication: HRs=2.08-5.61, P-value<0.01). In contrast, the variants that formed these rare haplotypes individually exhibited much smaller effects. Functional annotation revealed extensive cis-regulatory DNA elements in BCa-related cells underlying the replicated rare haplotypes. Using phased, imputed genotypes from 30,064 cases and 25,282 controls in the DRIVE OncoArray case-control study, six of the 13 rare-loci associations were found generalizable (odds ratio estimates: 1.48-7.67, P-value<0.05). This study demonstrates the complementary advantage of utilizing rare haplotypes to capture novel risk loci and suggests the potential for the discovery of more genetic elements contributing to cancer heritability as large datasets of germline whole-genome sequencing become available.
With mounting interest in translating genome-wide association study (GWAS) hits from large meta-analyses (meta-GWAS) in diverse clinical settings, evaluating their generalizability in target populations is crucial. Here, we consider long-term survivors of childhood cancers from the St. Jude Lifetime Cohort Study, and we show the limited generalizability of 1,376 robust SNP associations reported in the general population across 12 complex anthropometric and cardiometabolic phenotypes (n ¼ 2,231; observedto-expected replication ratio ¼ 0.70, p ¼ 6.2 3 10 À8 ). An examination of five comparable phenotypes in a second independent cohort of survivors from the Childhood Cancer Survivor Study corroborated the overall limited generalizability of meta-GWAS hits to survivors (n ¼ 4,212; observed-to-expected replication ratio ¼ 0.55, p ¼ 5.6 3 10 À15 ). Finally, in direct comparisons of survivor samples against independent equivalently powered general population samples from the UK Biobank, we consistently observed lower meta-GWAS hit replication rates and poorer polygenic risk score predictive performance in survivor samples for multiple phenotypes. As a possible explanation, we found that meta-GWAS hits were less likely to be replicated in survivors who had been exposed to cancer therapies that are associated with phenotype risk. Examination of complementary DNA methylation data in a subset of survivors revealed that treatment-related methylation patterns at genomic sites linked to meta-GWAS hits may disrupt established genetic signals in survivors.
doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
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