Explore the vast range of titles available.

Drug-induced QT prolongation (diLQTS), and subsequent risk of torsade de pointes, is a major concern with use of many medications, including for non-cardiac conditions. The possibility that genetic risk, in the form of polygenic risk scores (PGS), could be integrated into prediction of risk of diLQTS has great potential, although it is unknown how genetic risk is related to clinical risk factors as might be applied in clinical decision-making. In this study, we examined the PGS for QT interval in 2500 subjects exposed to a known QT-prolonging drug on prolongation of the QT interval over 500ms on subsequent ECG using electronic health record data. We found that the normalized QT PGS was higher in cases than controls (0.212±0.954 vs. -0.0270±1.003, P = 0.0002), with an unadjusted odds ratio of 1.34 (95%CI 1.17–1.53, P<0.001) for association with diLQTS. When included with age and clinical predictors of QT prolongation, we found that the PGS for QT interval provided independent risk prediction for diLQTS, in which the interaction for high-risk diagnosis or with certain high-risk medications (amiodarone, sotalol, and dofetilide) was not significant, indicating that genetic risk did not modify the effect of other risk factors on risk of diLQTS. We found that a high-risk cutoff (QT PGS ≥ 2 standard deviations above mean), but not a low-risk cutoff, was associated with risk of diLQTS after adjustment for clinical factors, and provided one method of integration based on the decision-tree framework. In conclusion, we found that PGS for QT interval is an independent predictor of diLQTS, but that in contrast to existing theories about repolarization reserve as a mechanism of increasing risk, the effect is independent of other clinical risk factors. More work is needed for external validation in clinical decision-making, as well as defining the mechanism through which genes that increase QT interval are associated with risk of diLQTS.

Purpose Little is known about how many insured patients receive pharmacogenetic testing. We describe trends of single-gene pharmacogenetic testing in a US managed care population, and demographic and clinical characteristics of patients who received a test. Methods We leveraged a random sample of nearly 11 million patients from a data set of paid medical and pharmacy claims to identify patients with at least one claim indicating receipt of at least one of these single-gene pharmacogenetic tests: CYP2C19 , CYP2D6 , CYP2C9 , VKORC1 , UGT1A1 , and HLA class 1 typing. Results From 1 January 2013 to 30 September 2017, 5712 patients received at least one pharmacogenetic test (55% female; mean age = 43 years). The median number of tests per patient was 3 (mean = 2.7, max = 12); 54% were processed through Managed Medicare/Medicaid, while 45% were processed through commercial insurance. The total number of pharmacogenetic tests received more than doubled from 2013 ( n  = 1955) to 2015 ( n  = 4192), then decreased slightly in 2016 ( n  = 3946). The most common test was CYP2C19 ( n  = 4719), and “long-term (current) use of other medications” was the most common diagnosis. Conclusion Pharmacogenetic testing through patients’ insurance was low, but more than doubled from 2013 to 2016. This study highlights the need to better understand utilization patterns and insurance coverage for pharmacogenetic tests.

Since the initial reported discovery of SARS-CoV-2 in late 2019, genomic surveillance has been an important tool to understand its transmission and evolution. Here, we sought to describe the underlying regional phylodynamics before and during a rapid spreading event that was documented by surveillance protocols of the United States Air Force Academy (USAFA) in late October-November of 2020. We used replicate long-read sequencing on Colorado SARS-CoV-2 genomes collected July through November 2020 at the University of Colorado Anschutz Medical campus in Aurora and the United States Air Force Academy in Colorado Springs. Replicate sequencing allowed rigorous validation of variation and placement in a phylogenetic relatedness network. We focus on describing the phylodynamics of a lineage that likely originated in the local Colorado Springs community and expanded rapidly over the course of two months in an outbreak within the well-controlled environment of the United States Air Force Academy. Divergence estimates from sampling dates indicate that the SARS-CoV-2 lineage associated with this rapid expansion event originated in late October 2020. These results are in agreement with transmission pathways inferred by the United States Air Force Academy, and provide a window into the evolutionary process and transmission dynamics of a potentially dangerous but ultimately contained variant.

Background Recent deliberations by Australian public health researchers and practitioners produced an ethical framework of how decisions should be made to distribute pandemic influenza vaccine. The outcome of the deliberations was that the population should be considered in two categories, Level 1 and Level 2, with Level 1 groups being offered access to the pandemic influenza vaccine before other groups. However, the public health researchers and practitioners recognised the importance of making space for public opinion and sought to understand citizens values and preferences, especially First Nations peoples. Methods We conducted First Nations Community Panels in two Australian locations in 2019 to assess First Nations people’s informed views through a deliberative process on pandemic influenza vaccination distribution strategies. Panels were asked to make decisions on priority levels, coverage and vaccine doses. Results Two panels were conducted with eighteen First Nations participants from a range of ages who were purposively recruited through local community networks. Panels heard presentations from public health experts, cross-examined expert presenters and deliberated on the issues. Both panels agreed that First Nations peoples be assigned Level 1 priority, be offered pandemic influenza vaccination before other groups, and be offered two doses of vaccine. Reasons for this decision included First Nations people’s lives, culture and families are important; are at-risk of severe health outcomes; and experience barriers and challenges to accessing safe, quality and culturally appropriate healthcare. We found that communication strategies, utilising and upskilling the First Nations health workforce, and targeted vaccination strategies are important elements in pandemic preparedness and response with First Nations peoples. Conclusions First Nations Community Panels supported prioritising First Nations peoples for pandemic influenza vaccination distribution and offering greater protection by using a two-dose full course to fewer people if there are initial supply limitations, instead of one dose to more people, during the initial phase of the vaccine roll out. The methodology and findings can help inform efforts in planning for future pandemic vaccination strategies for First Nations peoples in Australia.

As whole exome sequencing (WES) becomes more widely used in the clinical realm, a wealth of unanalyzed information will be routinely generated. Using WES read depth data to predict copy number variation (CNV) could extend the diagnostic utility of this previously underutilized data by providing clinically important information such as previously unsuspected deletions or duplications. We evaluated ExomeDepth, a free R package, in addition to an aneuploidy prediction method, to detect CNVs in WES data. First, in a blinded pilot study, five out of five genomic alterations were correctly identified from clinical samples with previously defined chromosomal gains or losses, including submicroscopic deletions, duplications, and chromosomal trisomy. We then examined CNV calls among 53 patients participating in the NCGENES research study and undergoing WES, who had existing clinical chromosomal microarray (CMA) data that could be used for validation. For unique CNVs that overlap well with WES coverage regions, sensitivity was 89% for deletions and 65% for duplications. While specificity of the algorithm calls remains a concern, this is less of an issue at high threshold filtering levels. When applied to all 672 patients from the exome sequencing study, ExomeDepth identified eleven diagnostically relevant CNVs ranging in size from a two exon deletion to whole chromosome duplications, as well as numerous other CNVs with varying clinical significance. This opportunistic analysis of WES data yields an additional 1.6% of patients in this study with pathogenic or likely pathogenic CNVs that are clinically relevant to their phenotype as well as clinically relevant secondary findings. Finally, we demonstrate the potential value of copy number analysis in cases where a single heterozygous likely or known pathogenic single nucleotide alteration is identified in a gene associated with an autosomal recessive condition.

As genome-scale sequencing is increasingly applied in clinical scenarios, a wide variety of genomic findings will be discovered as secondary or incidental findings, and there is debate about how they should be handled. The clinical actionability of such findings varies, necessitating standardized frameworks for a priori decision making about their analysis. We established a semiquantitative metric to assess five elements of actionability: severity and likelihood of the disease outcome, efficacy and burden of intervention, and knowledge base, with a total score from 0 to 15. The semiquantitative metric was applied to a list of putative actionable conditions, the list of genes recommended by the American College of Medical Genetics and Genomics (ACMG) for return when deleterious variants are discovered as secondary/incidental findings, and a random sample of 1,000 genes. Scores from the list of putative actionable conditions (median = 12) and the ACMG list (median = 11) were both statistically different than the randomly selected genes (median = 7) (P < 0.0001, two-tailed Mann-Whitney test). Gene–disease pairs having a score of 11 or higher represent the top quintile of actionability. The semiquantitative metric effectively assesses clinical actionability, promotes transparency, and may facilitate assessments of clinical actionability by various groups and in diverse contexts.

In recent years, the genomics community has witnessed the growth of large research biobanks, which collect DNA samples for research purposes. Depending on how and where the samples are genotyped, biobanks also offer the potential opportunity to return actionable genomic results to the clinical setting. We developed a preemptive clinical pharmacogenomic implementation initiative via a health system-wide research biobank at the University of Colorado. Here, we describe how preemptive return of clinical pharmacogenomic results via a research biobank is feasible, particularly when coupled with strong institutional support to maximize the impact and efficiency of biobank resources, a multidisciplinary implementation team, automated clinical decision support tools, and proactive strategies to engage stakeholders early in the clinical decision support tool development process.

Actionable drug–gene pairs relevant to depression treatment include CYP2D6 and CYP2C19 with specific antidepressants. While clinical use of pharmacogenetic testing is growing, little is known about pharmacogenetic testing for depression treatment in managed care. We determined the incidence of single‐gene CYP2D6 and CYP2C19 testing following a new depression episode among US managed care patients, and described characteristics and antidepressant use of patients receiving tests. We used paid medical and pharmacy claims for patients from commercial health plans in the US. For adult patients with a new depression episode from January 1, 2013 to June 30, 2018, we identified covered claims for single‐gene CYP2D6 and CYP2C19 pharmacogenetic tests and antidepressant fills. Fewer than 1% (n = 1795) of the depressed cohort (n = 438,534) received a single‐gene CYP2D6 or CYP2C19 test through their insurance within 365 days of their earliest depression episode. The percentage of patients who received a test nearly tripled from 0.2% in 2013 to 0.5% in 2014 before plateauing at 0.4% from 2014 to 2017. Among the patients who received a single‐gene CYP2D6 or CYP2C19 test and filled an antidepressant within 365 days of their depression diagnosis, up to 30% may have had their initial antidepressant informed by the test result. Our findings describe the use of antidepressants before and after pharmacogenetic testing, which is clinically relevant as pharmacogenomic testing becomes more common in clinical practice. Our study also emphasizes the need for procedure and billing codes that capture multiple‐gene panel tests to be more widely implemented in administrative databases.

This study explored Aboriginal and Torres Strait Islander peoples' experiences receiving Aboriginal cultural support from a public health unit in Hunter New England Local Health District in New South Wales. Using an Indigenist research approach, an online survey was conducted as well as yarning with Aboriginal and Torres Strait Islander people who had received cultural support while in isolation during the COVID-19 pandemic. Non-Aboriginal parents and carers of Aboriginal children were also eligible. Of 3,819 eligible individuals, 70 surveys were received with 55 valid responses after excluding 15. Using purposive sampling, 60 individuals were invited to participate in a yarn. Fifty-five participants completed the online survey and reported that the Aboriginal cultural support model they received was helpful and supportive. Yarns revealed valuable insights and lessons learnt for future pandemics. Three themes emerged: 1) cultural and community obligation, 2) culturally centred COVID-19 support and 3) accessing trusted COVID-19 information. This study highlighted the importance of Aboriginal-led pandemic responses. Embedding Aboriginal cultural support into public health responses enables tailored communication, strengthens relationships with Aboriginal communities and reinforces Aboriginal leadership.

IntroductionFirst Nations Peoples of Australia have not been included in the development nor prioritised in pre-2009 pandemic plans despite being a priority population in Australian health policy. Marginalised groups experience amplified barriers and systemic disadvantage in emergencies, however, their voices have not been heard in past pandemic responses. Through effective engagement with disadvantaged and oppressed groups, health authorities can gain a deeper understanding of how to design and implement pandemic control strategies. There have been limited studies with First Nations Peoples that has focused on pandemic planning and response strategies. Deliberative inclusive approaches such as citizens juries have been a way to uncover public perceptions.MethodsQualitative thematic research methods were used to conduct the study. We convened five First Nations Community Panels in three locations in Australia between 2019 and 2020. We used an Indigenist research approach, community-based Participatory Action Research framework and ‘yarning’ to understand whether Community Panels were an acceptable and appropriate way of engaging First Nations Peoples. Forty First Nations participants were purposively recruited through local and cultural networks. Panels heard evidence supporting various pandemic response strategies, and cross-questioned public health experts.ResultsAll 40 participants from the 5 panels verbally indicated strong support of the Community Panels approach as an effective way of engaging First Nations Peoples in making decisions about pandemic planning and response strategies. The main theme of ‘respect’ centred on the overarching principle that First Nations Peoples are important in the context of continuation of culture and ongoing political resistance.ConclusionFirst Nations Community Panels are a way of enabling active participation of First Nations peoples, increasing knowledge and understanding, and a way for government and policymakers to respectfully listen to First Nations opinions and values.