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SummaryThe maturation of genomic surveillance in the past decade has enabled tracking of the emergence and spread of epidemics at an unprecedented level. During the COVID-19 pandemic, for example, genomic data revealed that local epidemics varied considerably in the frequency of SARS-CoV-2 lineage importation and persistence, likely due to a combination of COVID-19 restrictions and changing connectivity. Here, we show that local COVID-19 epidemics are driven by regional transmission, including across international boundaries, but can become increasingly connected to distant locations following the relaxation of public health interventions. By integrating genomic, mobility, and epidemiological data, we find abundant transmission occurring between both adjacent and distant locations, supported by dynamic mobility patterns. We find that changing connectivity significantly influences local COVID-19 incidence. Our findings demonstrate a complex meaning of ‘local’ when investigating connected epidemics and emphasize the importance of collaborative interventions for pandemic prevention and mitigation.

BackgroundThe uptake of nirmatrelvir plus ritonavir (NPR) in patients with coronavirus disease 2019 (COVID-19) has been limited by concerns around the rebound phenomenon despite the scarcity of evidence around its epidemiology. The purpose of this study was to prospectively compare the epidemiology of rebound in NPR-treated and untreated participants with acute COVID-19 infection.MethodsWe designed a prospective, observational study in which participants who tested positive for COVID-19 and were clinically eligible for NPR were recruited to be evaluated for either viral or symptom clearance and rebound. Participants were assigned to the treatment or control group based on their decision to take NPR. Following initial diagnosis, both groups were provided 12 rapid antigen tests and asked to test on a regular schedule for 16 days and answer symptom surveys. Viral rebound based on test results and COVID-19 symptom rebound based on patient-reported symptoms were evaluated.ResultsViral rebound incidence was 14.2% in the NPR treatment group (n = 127) and 9.3% in the control group (n = 43). Symptom rebound incidence was higher in the treatment group (18.9%) compared to controls (7.0%). There were no notable differences in viral rebound by age, gender, preexisting conditions, or major symptom groups during the acute phase or at the 1-month interval.ConclusionsThis preliminary report suggests that rebound after clearance of test positivity or symptom resolution is higher than previously reported. However, notably we observed a similar rate of rebound in both the NPR treatment and control groups. Large studies with diverse participants and extended follow-up are needed to better understand the rebound phenomena.

We developed a smartphone application, MyGeneRank, to conduct a prospective observational cohort study (NCT03277365) involving the automated generation, communication, and electronic capture of response to a polygenic risk score (PRS) for coronary artery disease (CAD). Adults with a smartphone and an existing 23andMe genetic profiling self-referred to the study. We evaluated self-reported actions taken in response to personal CAD PRS information, with special interest in the initiation of lipid-lowering therapy. 19% (721/3,800) of participants provided complete responses for baseline and follow-up use of lipid-lowering therapy. 20% (n = 19/95) of high CAD PRS vs 7.9% (n = 8/101) of low CAD PRS participants initiated lipid-lowering therapy at follow-up (p-value = 0.002). Both the initiation of statin and non-statin lipid-lowering therapy was associated with degree of CAD PRS: 15.2% (n = 14/92) vs 6.0% (n = 6/100) for statins (p-value = 0.018) and 6.8% (n = 8/118) vs 1.6% (n = 2/123) for non-statins (p-value = 0.022) in high vs low CAD PRS, respectively. High CAD PRS was also associated with earlier initiation of lipid lowering therapy (average age of 52 vs 65 years in high vs low CAD PRS respectively, p-value = 0.007). Overall, degree of CAD PRS was associated with use of any lipid-lowering therapy at follow-up: 42.4% (n = 56/132) vs 28.5% (n = 37/130) (p-value = 0.009). We find that digital communication of personal CAD PRS information is associated with increased and earlier lipid-lowering initiation in individuals of high CAD PRS. Loss to follow-up is the primary limitation of this study. Alternative communication routes, and long-term studies with EHR-based outcomes are needed to understand the generalizability and durability of this finding.

The degree to which polygenic risk scores (PRS) influence preventive health is the subject of debate, with few prospective studies completed to date. We developed a smartphone application for the prospective and automated generation, communication, and electronic capture of response to a PRS for coronary artery disease (CAD). We evaluated self-reported actions taken in response to personal CAD PRS information, with special interest in the initiation of lipid lowering therapy (NCT03277365). 20% of high genetic risk (n=95) vs 7.9% of low genetic risk individuals (n=101) initiated lipid lowering therapy at follow-up (p-value = 0.002). The initiation of both statin and non-statin lipid lowering therapy was associated with degree of genetic risk – 15.2% (n=92) vs 6.0% (n=100) for statins (p-value = 0.018) and 6.8% (n=118) vs 1.6% (n=123) for non-statins (p-value = 0.022) in high vs low genetic risk, respectively. Overall, degree of genetic risk was associated with use of any lipid lowering therapy at follow-up - 42.4% (n=132) vs 28.5% (n=130) (p-value = 0.009). We also find that CAD PRS information is perceived to be understandable, actionable, and does not induce health anxiety.

The emergence of the COVID-19 epidemic in the United States (U.S.) went largely undetected due to inadequate testing. New Orleans experienced one of the earliest and fastest accelerating outbreaks, coinciding with Mardi Gras. To gain insight into the emergence of SARS-CoV-2 in the U.S. and how large-scale events accelerate transmission, we sequenced SARS-CoV-2 genomes during the first wave of the COVID-19 epidemic in Louisiana. We show that SARS-CoV-2 in Louisiana had limited diversity compared to other U.S. states, and that one introduction of SARS-CoV-2 led to almost all of the early transmission in Louisiana. By analyzing mobility and genomic data, we show that SARS-CoV-2 was already present in New Orleans before Mardi Gras, and the festival dramatically accelerated transmission. Our study provides an understanding of how superspreading during large-scale events played a key role during the early outbreak in the U.S. and can greatly accelerate epidemics., Genomic and epidemiological analyses provide a clearer picture of one of the earliest SARS-CoV-2 superspreader events in the United States in accelerating transmission, with a single introduction of the virus being responsible for most cases during this period.

This article critically appraises the ethical and legal duties to disclose findings to the family members of research participants. These family members stand to benefit in important ways from discoveries that can inform their own health and reproductive risks. However, careful appreciation of how medical research differs from clinical practice and of the uncertainties at stake in genomic research complicates any warning to relatives. Research laboratories should generally be immune from liability for failing to diagnose or disclose a genetic disorder in time to prevent adverse outcomes for a participant's family members or to return properly interpreted test results for even direct findings under investigation, let alone incidental ones. The only exception is where warning relatives of medical risks is very likely to prevent imminent harm and would not override known participant wishes. Genomic autopsy studies for sudden death satisfy these conditions of life-saving potential for relatives without disrespect to subjects. These are among the rare instances in which we conclude that offering results to family members is not just permissible but obligatory, not just as a moral matter but as a legal one.

The direct to consumer (DTC)2 genetic testing market was initiated in 2007 with the introduction of 23andMe. Since then, there has been marked expansion and, at the same time, considerable efforts to scrutinize the potential benefits and harms of such testing (1). The various tests are heterogeneous, with output ranging from medical data to ancestry to lifestyle. Along the way, fitness-centered DTC genetic tests have cropped up, encouraging consumers to pay, as we will briefly describe here, high costs for what we feel to be low value information. These tests promise insights about nutrition, healthy aging, weight loss, and athletic aptitude (even for specific sports). They market faux scientific authority, engendering confusion and the potential for harm, no less diminishing consumer confidence in validated, actionable, genetic tests. The genetic testing market is currently divided into 2 main categories with a couple of exceptions that operate in both arenas. Clinical tests require that a physician order each test, are subject to regulatory oversight, and are aimed at diagnosing or screening for mutations related to specific medical conditions. In contrast, DTC tests are purchased without any need for physician involvement. Current surveys identify approximately 40 companies offering DTC fitness genetic tests (2) and several companies that serve as a marketplace for purchasing a variety of such tests interpreted by third parties. Although registries exist to provide some assistance for medical genetics professionals to choose between the approximately 75000 clinical genetic tests available (3), there is no such resource for consumers. DTC genetic test prices range from under $30 to well over $1000. The less expensive tests are generally for individual single nucleotide variants, and marketing by some DTC companies drives sales of multiple tests per customer. The DTC genetic testing market is estimated to total about $100 million in 2017, with …

Background Whole-exome sequencing (WES) has become an efficient diagnostic test for patients with likely monogenic conditions such as rare idiopathic diseases or sudden unexplained death. Yet, many cases remain undiagnosed. Here, we report the added diagnostic yield achieved for 101 WES cases re-analyzed 1 to 7 years after initial analysis. Methods Of the 101 WES cases, 51 were rare idiopathic disease cases and 50 were postmortem “molecular autopsy” cases of early sudden unexplained death. Variants considered for reporting were prioritized and classified into three groups: (1) diagnostic variants, pathogenic and likely pathogenic variants in genes known to cause the phenotype of interest; (2) possibly diagnostic variants, possibly pathogenic variants in genes known to cause the phenotype of interest or pathogenic variants in genes possibly causing the phenotype of interest; and (3) variants of uncertain diagnostic significance, potentially deleterious variants in genes possibly causing the phenotype of interest. Results Initial analysis revealed diagnostic variants in 13 rare disease cases (25.4%) and 5 sudden death cases (10%). Re-analysis resulted in the identification of additional diagnostic variants in 3 rare disease cases (5.9%) and 1 sudden unexplained death case (2%), which increased our molecular diagnostic yield to 31.4% and 12%, respectively. Conclusions The basis of new findings ranged from improvement in variant classification tools, updated genetic databases, and updated clinical phenotypes. Our findings highlight the potential for re-analysis to reveal diagnostic variants in cases that remain undiagnosed after initial WES.

SUMMARYPrimary prevention of coronary artery disease (CAD) is important for individuals at increased risk, and largely consists of healthy lifestyle modifications and initiation of medications when appropriate – including statins. Defining the inherent risk for any given individual typically relies on traditional risk factors established decades ago by the Framingham Heart Study. Unfortunately, recent studies have indicated that these traditional clinical risk factors systematically overestimate the risk of CAD across all major ancestries. This has increased the number of patients that would be eligible for statin therapy for the primary prevention of CAD but would likely receive little benefit and potentially incur negative consequences. On the other hand, researchers have demonstrated that genetic factors can effectively identify a subset of high risk individuals, and that the benefit from statin therapy is greatest among individuals with the highest genetic risk score (GRS). These individuals also receive the greatest absolute benefit from healthy lifestyle choices, being able to titrate their risk to normal levels despite high genetic predisposition. However, it is not yet possible for the average individual to discover their genetic risk because no tools are currently available to make such a determination. Here, we present a free mobile app – MyGeneRank – that can provide this information. Individuals may choose to use this knowledge to complement traditional risk assessments, and make critical decisions regarding lifelong statin therapy and lifestyle changes. As of 1/25/2017, MyGeneRank is currently in closed beta and will soon be available to the public.

Purpose: Nail-Patella syndrome is a dominantly inherited genetic disorder characterized by abnormalities of the nails, knees, elbows, and pelvis. Nail abnormalities are the most constant feature of Nail-Patella syndrome. Pathogenic mutations in a single gene, LMX1B, a mesenchymal determinant of dorsal-ventral patterning, explain approximately 95% of Nail-Patella syndrome cases. However, 5% of cases remain unexplained. Methods: Here, we present exome sequencing and analysis of four generations of a family with a dominantly inherited Nail-Patella-like disorder (nail dysplasia with some features of Nail-Patella syndrome) who tested negative for LMX1B mutation. Results: We identify a loss-of-function mutation in WIF1 (NM_007191 p.W15*), which is involved in mesoderm segmentation, as the suspected cause of the Nail-Patella-like disorder observed in this family. Conclusions: Mutation of WIF1 is a potential novel cause of a Nail-Patella-like disorder. Testing of additional patients negative for LMX1B mutation is needed to confirm this finding and further clarify the phenotype. Genet Med advance online publication 06 April 2017