Publications by authors named "Iftikhar J Kullo"

287 Publications

Do research participants share genomic screening results with family members?

J Genet Couns 2021 Oct 19. Epub 2021 Oct 19.

Division of Genetics and Genomics and the Manton Center for Orphan Diseases Research, Boston Children's Hospital, Boston, MA, USA.

The public health impact of genomic screening can be enhanced by cascade testing. However, cascade testing depends on communication of results to family members. While the barriers and facilitators of family communication have been researched following clinical genetic testing, the factors impacting the dissemination of genomic screening results are unknown. Using the pragmatic Electronic Medical Records and Genomics Network-3 (eMERGE-3) study, we explored the reported sharing practices of participants who underwent genomic screening across the United States. Six eMERGE-3 sites returned genomic screening results for mostly dominant medically actionable disorders and surveyed adult participants regarding communication of results with first-degree relatives. Across the sites, 279 participants completed a 1-month and/or 6-month post-results survey. By 6 months, only 34% of the 156 respondents shared their results with all first-degree relatives and 4% did not share with any. Over a third (39%) first-degree relatives were not notified of the results. Half (53%) of participants who received their results from a genetics provider shared them with all first-degree relatives compared with 11% of participants who received their results from a non-genetics provider. The most frequent reasons for sharing were a feeling of obligation (72%) and that the information could help family members make medical decisions (72%). The most common reasons indicated for not sharing were that the family members were too young (38%), or they were not in contact (25%) or not close to them (25%). These data indicate that the professional returning the results may impact sharing patterns, suggesting that there is a need to continue to educate healthcare providers regarding approaches to facilitate sharing of genetic results within families. Finally, these data suggest that interventions to increase sharing may be universally effective regardless of the origin of the genetic result.
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http://dx.doi.org/10.1002/jgc4.1511DOI Listing
October 2021

Penalized mediation models for multivariate data.

Genet Epidemiol 2021 Oct 19. Epub 2021 Oct 19.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA.

Statistical methods to integrate multiple layers of data, from exposures to intermediate traits to outcome variables, are needed to guide interpretation of complex data sets for which variables are likely contributing in a causal pathway from exposure to outcome. Statistical mediation analysis based on structural equation models provide a general modeling framework, yet they can be difficult to apply to high-dimensional data and they are not automated to select the best fitting model. To overcome these limitations, we developed novel algorithms and software to simultaneously evaluate multiple exposure variables, multiple intermediate traits, and multiple outcome variables. Our penalized mediation models are computationally efficient and simulations demonstrate that they produce reliable results for large data sets. Application of our methods to a study of vascular disease demonstrates their utility to identify novel direct effects of single-nucleotide polymorphisms (SNPs) on coronary heart disease and peripheral artery disease, while disentangling the effects of SNPs on the intermediate risk factors including lipids, cigarette smoking, systolic blood pressure, and type 2 diabetes.
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http://dx.doi.org/10.1002/gepi.22433DOI Listing
October 2021

Genetic investigation of fibromuscular dysplasia identifies risk loci and shared genetics with common cardiovascular diseases.

Nat Commun 2021 10 15;12(1):6031. Epub 2021 Oct 15.

Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.

Fibromuscular dysplasia (FMD) is an arteriopathy associated with hypertension, stroke and myocardial infarction, affecting mostly women. We report results from the first genome-wide association meta-analysis of six studies including 1556 FMD cases and 7100 controls. We find an estimate of SNP-based heritability compatible with FMD having a polygenic basis, and report four robustly associated loci (PHACTR1, LRP1, ATP2B1, and LIMA1). Transcriptome-wide association analysis in arteries identifies one additional locus (SLC24A3). We characterize open chromatin in arterial primary cells and find that FMD associated variants are located in arterial-specific regulatory elements. Target genes are broadly involved in mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, central to vascular contraction. We find significant genetic overlap between FMD and more common cardiovascular diseases and traits including blood pressure, migraine, intracranial aneurysm, and coronary artery disease.
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http://dx.doi.org/10.1038/s41467-021-26174-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521585PMC
October 2021

Genome-Wide Association Study of Peripheral Artery Disease.

Circ Genom Precis Med 2021 10 4;14(5):e002862. Epub 2021 Oct 4.

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health (A.S., J.C.H.), University of Oxford, United Kingdom.

Background: Peripheral artery disease (PAD) affects >200 million people worldwide and is associated with high mortality and morbidity. We sought to identify genomic variants associated with PAD overall and in the contexts of diabetes and smoking status.

Methods: We identified genetic variants associated with PAD and then meta-analyzed with published summary statistics from the Million Veterans Program and UK Biobank to replicate their findings. Next, we ran stratified genome-wide association analysis in ever smokers, never smokers, individuals with diabetes, and individuals with no history of diabetes and corresponding interaction analyses, to identify variants that modify the risk of PAD by diabetic or smoking status.

Results: We identified 5 genome-wide significant ( ≤5×10) associations with PAD in 449 548 (N=12 086) individuals of European ancestry near ) loci (which overlapped previously reported associations). Meta-analysis with variants previously associated with PAD showed that 18 of 19 published variants remained genome-wide significant. In individuals with diabetes, rs116405693 at the ) locus was associated with PAD (odds ratio [95% CI], 1.51 [1.32-1.74], =2.5×10, =5.3×10). Furthermore, in smokers, rs12910984 at the locus was associated with PAD (odds ratio [95% CI], 1.15 [1.11-1.19], =9.3×10, =3.9×10).

Conclusions: Our analyses confirm the published genetic associations with PAD and identify novel variants that may influence susceptibility to PAD in the context of diabetes or smoking status.
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http://dx.doi.org/10.1161/CIRCGEN.119.002862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8542067PMC
October 2021

Cost-effectiveness of cascade genetic testing for familial hypercholesterolemia in the United States: A simulation analysis.

Am J Prev Cardiol 2021 Dec 15;8:100245. Epub 2021 Aug 15.

Department of Cardiovascular Medicine and the Gonda Vascular Center, Mayo Clinic, Rochester, MN, United States.

There is no coordinated cascade testing program for familial hypercholesterolemia (FH) in the U.S. We evaluated the contemporary cost-effectiveness of cascade genetic testing relatives of FH probands with a pathogenic variant. A simulation model was created to simulate multiple family trees starting with progenitor individuals carrying a pathogenic variant for FH who were followed through several generations. This approach allowed us to examine a family tree that had grown sufficiently to have large numbers of relatives across multiple degrees of relatedness. The model estimated costs and life years gained (LYG) when cascade genetic testing was implemented for relatives of FH probands identified through standard care who were at or older than designated age thresholds (5, 10, 15, 20, 25, 30, 35, 40). Costs were valued in 2018 U.S. dollars. Future costs and LYG projected by the model were discounted at an annual rate of 3%. For 1st degree relatives, cascade testing at every age threshold resulted in a positive number of average LYG per person, though this number decreased as testing was started at higher age thresholds. Testing was not cost-effective if initiated at an age threshold of 40 and older but was cost-effective at younger age thresholds, with a discounted cost per LYG per person of less than $50,000. For 2nd degree relatives, testing was cost-effective with a screening age threshold of 10 but no longer cost-effective at a threshold of 15 or higher. In more distant relatives, cascade genetic testing was not beneficial or cost-effective. Based on our simulation model, cascade genetic testing for FH in the U.S. is cost-effective if started before age 40 in 1st degree relatives and before age 15 in 2nd degree relatives.
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http://dx.doi.org/10.1016/j.ajpc.2021.100245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403726PMC
December 2021

Familial hypercholesterolemia in Southeast and East Asia.

Am J Prev Cardiol 2021 Jun 12;6:100157. Epub 2021 Feb 12.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN USA.

Familial hypercholesterolemia (FH) is a relatively common autosomal dominant disorder associated with a significantly increased risk of coronary heart disease (CHD). Most (~85-90%) cases are due to pathogenic variants in the LDL-receptor gene (), while the remaining are due to pathogenic variants in the apolipoprotein B () and proprotein convertase subtilisin/kexin type 9 () genes, though the proportion may vary depending on geographic location. Even though at least a quarter of the world's FH population lives in Southeast and East Asia, there are substantial gaps in knowledge regarding the epidemiology of FH due to low awareness, the absence of national screening programs, and limited availability of genetic testing. In this review, we discuss the most recent and relevant information available related to diagnostic criteria, prevalence, awareness, clinical characteristics, genetic epidemiology, and treatment in the FH population of Southeast and East Asia. Increasing awareness and improving the diagnosis and management of FH will reduce the burden of premature CHD in these regions of the world.
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http://dx.doi.org/10.1016/j.ajpc.2021.100157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315601PMC
June 2021

Quantitative disease risk scores from EHR with applications to clinical risk stratification and genetic studies.

NPJ Digit Med 2021 Jul 23;4(1):116. Epub 2021 Jul 23.

Department of Biostatistics, Columbia University, New York, NY, USA.

Labeling clinical data from electronic health records (EHR) in health systems requires extensive knowledge of human expert, and painstaking review by clinicians. Furthermore, existing phenotyping algorithms are not uniformly applied across large datasets and can suffer from inconsistencies in case definitions across different algorithms. We describe here quantitative disease risk scores based on almost unsupervised methods that require minimal input from clinicians, can be applied to large datasets, and alleviate some of the main weaknesses of existing phenotyping algorithms. We show applications to phenotypic data on approximately 100,000 individuals in eMERGE, and focus on several complex diseases, including Chronic Kidney Disease, Coronary Artery Disease, Type 2 Diabetes, Heart Failure, and a few others. We demonstrate that relative to existing approaches, the proposed methods have higher prediction accuracy, can better identify phenotypic features relevant to the disease under consideration, can perform better at clinical risk stratification, and can identify undiagnosed cases based on phenotypic features available in the EHR. Using genetic data from the eMERGE-seq panel that includes sequencing data for 109 genes on 21,363 individuals from multiple ethnicities, we also show how the new quantitative disease risk scores help improve the power of genetic association studies relative to the standard use of disease phenotypes. The results demonstrate the effectiveness of quantitative disease risk scores derived from rich phenotypic EHR databases to provide a more meaningful characterization of clinical risk for diseases of interest beyond the prevalent binary (case-control) classification.
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http://dx.doi.org/10.1038/s41746-021-00488-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302667PMC
July 2021

Associations of Genetically Predicted Lp(a) (Lipoprotein [a]) Levels With Cardiovascular Traits in Individuals of European and African Ancestry.

Circ Genom Precis Med 2021 08 20;14(4):e003354. Epub 2021 Jul 20.

Department of Cardiovascular Medicine (B.A.S., O.D., M.S.S., I.J.K.), Mayo Clinic, Rochester, MN.

Background: Lp(a) (lipoprotein [a]) levels are higher in individuals of African ancestry (AA) than in individuals of European ancestry (EA). We examined associations of genetically predicted Lp(a) levels with (1) atherosclerotic cardiovascular disease subtypes: coronary heart disease, cerebrovascular disease, peripheral artery disease, and abdominal aortic aneurysm and (2) nonatherosclerotic cardiovascular disease phenotypes, stratified by ancestry.

Methods: We performed (1) Mendelian randomization analyses for previously reported cardiovascular associations and (2) Mendelian randomization-phenome-wide association analyses for novel associations. Analyses were stratified by ancestry in electronic Medical Records and Genomics, United Kingdom Biobank, and Million Veteran Program cohorts separately and in a combined cohort of 804 507 EA and 103 580 AA participants.

Results: In Mendelian randomization analyses using the combined cohort, a 1-SD genetic increase in Lp(a) level was associated with atherosclerotic cardiovascular disease subtypes in EA-odds ratio and 95% CI for coronary heart disease 1.28 (1.16-1.41); cerebrovascular disease 1.14 (1.07-1.21); peripheral artery disease 1.22 (1.11-1.34); abdominal aortic aneurysm 1.28 (1.17-1.40); in AA, the effect estimate was lower than in EA and nonsignificant for coronary heart disease 1.11 (0.99-1.24) and cerebrovascular disease 1.06 (0.99-1.14) but similar for peripheral artery disease 1.16 (1.01-1.33) and abdominal aortic aneurysm 1.34 (1.11-1.62). In EA, a 1-SD genetic increase in Lp(a) level was associated with aortic valve disorders 1.34 (1.10-1.62), mitral valve disorders 1.18 (1.09-1.27), congestive heart failure 1.12 (1.05-1.19), and chronic kidney disease 1.07 (1.01-1.14). In AA, no significant associations were noted for aortic valve disorders 1.08 (0.94-1.25), mitral valve disorders 1.02 (0.89-1.16), congestive heart failure 1.02 (0.95-1.10), or chronic kidney disease 1.05 (0.99-1.12). Mendelian randomization-phenome-wide association analyses identified novel associations in EA with arterial thromboembolic disease, nonaortic aneurysmal disease, atrial fibrillation, cardiac conduction disorders, and hypertension.

Conclusions: Many cardiovascular associations of genetically increased Lp(a) that were significant in EA were not significant in AA. Lp(a) was associated with atherosclerotic cardiovascular disease in four major arterial beds in EA but only with peripheral artery disease and abdominal aortic aneurysm in AA. Additionally, novel cardiovascular associations were detected in EA.
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http://dx.doi.org/10.1161/CIRCGEN.120.003354DOI Listing
August 2021

A call for training programmes in cardiovascular genomics.

Nat Rev Cardiol 2021 Aug;18(8):539-540

Department of Cardiovascular Medicine and the Gonda Vascular Center, Mayo Clinic, Rochester, MN, USA.

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http://dx.doi.org/10.1038/s41569-021-00586-5DOI Listing
August 2021

Leveraging the Electronic Health Record to Address the COVID-19 Pandemic.

Mayo Clin Proc 2021 06 21;96(6):1592-1608. Epub 2021 Apr 21.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN; Gonda Vascular Center, Mayo Clinic, Rochester, MN. Electronic address:

The coronavirus disease 2019 (COVID-19) pandemic continues its global spread. Coordinated effort on a vast scale is required to halt its progression and to save lives. Electronic health record (EHR) data are a valuable resource to mitigate the COVID-19 pandemic. We review how the EHR could be used for disease surveillance and contact tracing. When linked to "omics" data, the EHR could facilitate identification of genetic susceptibility variants, leading to insights into risk factors, disease complications, and drug repurposing. Real-time monitoring of patients could enable early detection of potential complications, informing appropriate interventions and therapy. We reviewed relevant articles from PubMed, MEDLINE, and Google Scholar searches as well as preprint servers, given the rapidly evolving understanding of the COVID-19 pandemic.
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http://dx.doi.org/10.1016/j.mayocp.2021.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059945PMC
June 2021

Preferences for Updates on General Research Results: A Survey of Participants in Genomic Research from Two Institutions.

J Pers Med 2021 May 11;11(5). Epub 2021 May 11.

Johns Hopkins University Berman Institute of Bioethics, Baltimore, MD 21205, USA.

There is a need for multimodal strategies to keep research participants informed about study results. Our aim was to characterize preferences of genomic research participants from two institutions along four dimensions of general research result updates: content, timing, mechanism, and frequency.

Methods: We conducted a web-based cross-sectional survey that was administered from 25 June 2018 to 5 December 2018.

Results: 397 participants completed the survey, most of whom (96%) expressed a desire to receive research updates. Preferences with high endorsement included: update content (brief descriptions of major findings, descriptions of purpose and goals, and educational material); update timing (when the research is completed, when findings are reviewed, when findings are published, and when the study status changes); update mechanism (email with updates, and email newsletter); and update frequency (every three months). Hierarchical cluster analyses based on the four update preferences identified four profiles of participants with similar preference patterns. Very few participants in the largest profile were comfortable with budgeting less money for research activities so that researchers have money to set up services to send research result updates to study participants.

Conclusion: Future studies may benefit from exploring preferences for research result updates, as we have in our study. In addition, this work provides evidence of a need for funders to incentivize researchers to communicate results to participants.
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http://dx.doi.org/10.3390/jpm11050399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151672PMC
May 2021

Coronary Heart Disease Risk Associated with Primary Isolated Hypertriglyceridemia; a Population-Based Study.

J Am Heart Assoc 2021 06 25;10(11):e019343. Epub 2021 May 25.

Department of Cardiovascular Medicine Mayo Clinic Rochester MN.

Background Hypertriglyceridemia is associated with increased risk of coronary heart disease but the association is often attributed to concomitant metabolic abnormalities. We investigated the epidemiology of primary isolated hypertriglyceridemia (PIH) and associated cardiovascular risk in a population-based setting. Methods and Results We identified adults with at least one triglyceride level ≥500 mg/dL between 1998 and 2015 in Olmsted County, Minnesota. We also identified age- and sex-matched controls with triglyceride levels <150 mg/dL. There were 3329 individuals with elevated triglyceride levels; after excluding those with concomitant hypercholesterolemia, a secondary cause of high triglycerides, age <18 years or an incomplete record, 517 patients (49.4±14.0 years, 72.0% men) had PIH (triglyceride 627.6±183.6 mg/dL). The age- and sex-adjusted prevalence of PIH in adults was 0.80% (0.72-0.87); the diagnosis was recorded in 60%, 46% were on a lipid-lowering medication for primary prevention and a triglyceride level <150 mg/dL was achieved in 24.1%. The association of PIH with coronary heart disease was attenuated but remained significant after adjustment for demographic, socioeconomic, and conventional cardiovascular risk factors (hazard ratio [HR], 1.53; 95% CI, 1.06-2.20; = 0.022). There was no statistically significant association between PIH and cerebrovascular disease (HR, 1.06; 95% CI, 0.65-1.73, = 0.813), peripheral artery disease (HR, 1.27; 95% CI, 0.43-3.75; = 0.668), or the composite end point of all 3 (HR, 1.28; 95% CI, 0.92-1.80; =0.148) in adjusted models. Conclusions PIH was associated with incident coronary heart disease events (although there was attenuation after adjustment for conventional risk factors), supporting a causal role for triglycerides in coronary heart disease. The condition is relatively prevalent but awareness and control are low.
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http://dx.doi.org/10.1161/JAHA.120.019343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483538PMC
June 2021

Genomic considerations for FHIR®; eMERGE implementation lessons.

J Biomed Inform 2021 06 28;118:103795. Epub 2021 Apr 28.

Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Structured representation of clinical genetic results is necessary for advancing precision medicine. The Electronic Medical Records and Genomics (eMERGE) Network's Phase III program initially used a commercially developed XML message format for standardized and structured representation of genetic results for electronic health record (EHR) integration. In a desire to move towards a standard representation, the network created a new standardized format based upon Health Level Seven Fast Healthcare Interoperability Resources (HL7® FHIR®), to represent clinical genomics results. These new standards improve the utility of HL7® FHIR® as an international healthcare interoperability standard for management of genetic data from patients. This work advances the establishment of standards that are being designed for broad adoption in the current health information technology landscape.
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http://dx.doi.org/10.1016/j.jbi.2021.103795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8583906PMC
June 2021

"Who Doesn't Like Receiving Good News?" Perspectives of Individuals Who Received Genomic Screening Results by Mail.

J Pers Med 2021 Apr 21;11(5). Epub 2021 Apr 21.

Biomedical Ethics Research Program, Mayo Clinic, Rochester, MN 55901, USA.

As genomic sequencing expands to screen larger numbers of individuals, offering genetic counseling to everyone may not be possible. One approach to managing this limitation is for a genetic counselor to communicate clinically actionable results in person or by telephone, but report other results by mail. We employed this approach in a large genomic implementation study. In this paper, we describe participants' experiences receiving genomic screening results by mail. We conducted 50 semi-structured telephone interviews with individuals who received neutral genomic screening results by mail. Most participants were satisfied receiving neutral results by mail. Participants generally had a good understanding of results; however, a few participants had misunderstandings about their genomic screening results, including mistaken beliefs about their disease risk and the comprehensiveness of the test. No one reported plans to alter health behaviors, defer medical evaluations, or take other actions that might be considered medically problematic. Reporting neutral results by mail is unlikely to cause recipients distress or generate misunderstandings that may result in reduced vigilance in following recommended preventive health strategies. Nonetheless, some individuals may benefit from additional genetic counseling support to help situate their results in the context of personal concerns and illness experiences.
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http://dx.doi.org/10.3390/jpm11050322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142970PMC
April 2021

Genetic basis of hypercholesterolemia in adults.

NPJ Genom Med 2021 Apr 14;6(1):28. Epub 2021 Apr 14.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.

We investigated monogenic and polygenic causes of hypercholesterolemia in a population-based cohort, excluding secondary hypercholesterolemia, and using an established framework to identify pathogenic variants. We studied 1682 individuals (50.2 ± 8.6 years, 41.3% males) from southeast Minnesota with primary hypercholesterolemia (low-density lipoprotein cholesterol (LDL-C) ≥155 mg/dl in the absence of identifiable secondary causes). Familial hypercholesterolemia (FH) phenotype was defined as a Dutch Lipid Clinic Network (DLCN) score ≥6. Participants underwent sequencing of LDLR, APOB, and PCSK9, and genotyping of 12 LDL-C-associated single-nucleotide variants to construct a polygenic score (PGS) for LDL-C. The presence of a pathogenic/likely pathogenic variant was considered monogenic etiology and a PGS ≥90th percentile was considered polygenic etiology. The mean LDL-C level was 187.3 ± 32.3 mg/dl and phenotypic FH was present in 8.4% of the cohort. An identifiable genetic etiology was present in 17.1% individuals (monogenic in 1.5% and polygenic in 15.6%). Phenotypic and genetic FH showed poor overlap. Only 26% of those who met the clinical criteria of FH had an identifiable genetic etiology and of those with an identifiable genetic etiology only 12.9% met clinical criteria for FH. Genetic factors explained 7.4% of the variance in LDL-C. In conclusion, in adults with primary hypercholesterolemia, 17.1% had an identifiable genetic etiology and the overlap between phenotypic and genetic FH was modest.
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http://dx.doi.org/10.1038/s41525-021-00190-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046820PMC
April 2021

Penetrance and outcomes at 1-year following return of actionable variants identified by genome sequencing.

Genet Med 2021 07 6;23(7):1192-1201. Epub 2021 Apr 6.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.

Purpose: We estimated penetrance of actionable genetic variants and assessed near-term outcomes following return of results (RoR).

Methods: Participants (n = 2,535) with hypercholesterolemia and/or colon polyps underwent targeted sequencing of 68 genes and 14 single-nucleotide variants. Penetrance was estimated based on presence of relevant traits in the electronic health record (EHR). Outcomes occurring within 1-year of RoR were ascertained by EHR review. Analyses were stratified by tier 1 and non-tier 1 disorders.

Results: Actionable findings were present in 122 individuals and results were disclosed to 98. The average penetrance for tier 1 disorder variants (67%; n = 58 individuals) was higher than in non-tier 1 variants (46.5%; n = 58 individuals). After excluding 45 individuals (decedents, nonresponders, known genetic diagnoses, mosaicism), ≥1 outcomes were noted in 83% of 77 participants following RoR; 78% had a process outcome (referral to a specialist, new testing, surveillance initiated); 68% had an intermediate outcome (new test finding or diagnosis); 19% had a clinical outcome (therapy modified, risk reduction surgery). Risk reduction surgery occurred more often in participants with tier 1 than those with non-tier 1 variants.

Conclusion: Relevant phenotypic traits were observed in 57% whereas a clinical outcome occurred in 19% of participants with actionable genomic variants in the year following RoR.
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http://dx.doi.org/10.1038/s41436-021-01142-9DOI Listing
July 2021

Integrating Genomic Screening into Primary Care: Provider Experiences Caring for Latino Patients at a Community-Based Health Center.

J Prim Care Community Health 2021 Jan-Dec;12:21501327211000242

Mayo Clinic, Rochester, MN, USA.

Introduction: Minority communities have had limited access to advances in genomic medicine. Mayo Clinic and Mountain Park Health Center, a Federally Qualified Health Center in Phoenix, Arizona, partnered to assess the feasibility of offering genomic screening to Latino patients receiving care at a community-based health center. We examined primary care provider (PCP) experiences reporting genomic screening results and integrating those results into patient care.

Methods: We conducted open-ended, semi-structured interviews with PCPs and other members of the health care team charged with supporting patients who received positive genomic screening results. Interviews were recorded, transcribed, and analyzed thematically.

Results: Of the 500 patients who pursued genomic screening, 10 received results indicating a genetic variant that warranted clinical management. PCPs felt genomic screening was valuable to patients and their families, and that genomic research should strive to include underrepresented minorities. Providers identified multiple challenges integrating genomic sequencing into patient care, including difficulties maintaining patient contact over time; arranging follow-up medical care; and managing results in an environment with limited genetics expertise. Providers also reflected on the ethics of offering genomic sequencing to patients who may not be able to pursue diagnostic testing or follow-up care due to financial constraints.

Conclusions: Our results highlight the potential benefits and challenges of bringing advances in precision medicine to community-based health centers serving under-resourced populations. By proactively considering patient support needs, and identifying financial assistance programs and patient-referral mechanisms to support patients who may need specialized medical care, PCPs and other health care providers can help to ensure that precision medicine lives up to its full potential as a tool for improving patient care.
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http://dx.doi.org/10.1177/21501327211000242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975483PMC
June 2021

Usability of a Digital Registry to Promote Secondary Prevention for Peripheral Artery Disease Patients.

Mayo Clin Proc Innov Qual Outcomes 2021 Feb 28;5(1):94-102. Epub 2020 Nov 28.

Department of Cardiovascular Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN.

Objective: To evaluate usability of a quality improvement tool that promotes guideline-based care for patients with peripheral arterial disease (PAD).

Patients And Methods: The study was conducted from July 19, 2018, to August 21, 2019. We compared the usability of a PAD cohort knowledge solution (CKS) with standard management supported by an electronic health record (EHR). Two scenarios were developed for usability evaluation; the first for the PAD-CKS while the second evaluated standard EHR workflow. Providers were asked to provide opinions about the PAD-CKS tool and to generate a System Usability Scale (SUS) score. Metrics analyzed included time required, number of mouse clicks, and number of keystrokes.

Results: Usability evaluations were completed by 11 providers. SUS for the PAD-CKS was excellent at 89.6. Time required to complete 21 tasks in the CKS was 4 minutes compared with 12 minutes for standard EHR workflow (median,  = .002). Completion of CKS tasks required 34 clicks compared with 148 clicks for the EHR (median,  = .002). Keystrokes for CKS task completion was 8 compared with 72 for EHR (median,  = .004). Providers indicated that overall they found the tool easy to use and the PAD mortality risk score useful.

Conclusions: Usability evaluation of the PAD-CKS tool demonstrated time savings, a high SUS score, and a reduction of mouse clicks and keystrokes for task completion compared to standard workflow using the EHR. Provider feedback regarding the strengths and weaknesses also created opportunities for iterative improvement of the PAD-CKS tool.
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http://dx.doi.org/10.1016/j.mayocpiqo.2020.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930799PMC
February 2021

Improving reporting standards for polygenic scores in risk prediction studies.

Nature 2021 03 10;591(7849):211-219. Epub 2021 Mar 10.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Polygenic risk scores (PRSs), which often aggregate results from genome-wide association studies, can bridge the gap between initial discovery efforts and clinical applications for the estimation of disease risk using genetics. However, there is notable heterogeneity in the application and reporting of these risk scores, which hinders the translation of PRSs into clinical care. Here, in a collaboration between the Clinical Genome Resource (ClinGen) Complex Disease Working Group and the Polygenic Score (PGS) Catalog, we present the Polygenic Risk Score Reporting Standards (PRS-RS), in which we update the Genetic Risk Prediction Studies (GRIPS) Statement to reflect the present state of the field. Drawing on the input of experts in epidemiology, statistics, disease-specific applications, implementation and policy, this comprehensive reporting framework defines the minimal information that is needed to interpret and evaluate PRSs, especially with respect to downstream clinical applications. Items span detailed descriptions of study populations, statistical methods for the development and validation of PRSs and considerations for the potential limitations of these scores. In addition, we emphasize the need for data availability and transparency, and we encourage researchers to deposit and share PRSs through the PGS Catalog to facilitate reproducibility and comparative benchmarking. By providing these criteria in a structured format that builds on existing standards and ontologies, the use of this framework in publishing PRSs will facilitate translation into clinical care and progress towards defining best practice.
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http://dx.doi.org/10.1038/s41586-021-03243-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8609771PMC
March 2021

Experiences of Latino Participants Receiving Neutral Genomic Screening Results: A Qualitative Study.

Public Health Genomics 2021 Feb 16;24(1-2):44-53. Epub 2021 Feb 16.

Biomedical Ethics Research Program, Mayo Clinic, Rochester, Minnesota, USA,

Purpose: The aim of the study was to characterize experiences of Latino participants receiving genomic screening results.

Methods: Participants were recruited at a federally qualified health center in the USA. In-person, semi-structured interviews were conducted in either Spanish or English by a bilingual, bicultural interviewer. Questions focused on motivations for pursuing genomic sequencing, concerns about receiving genomic screening results, and perceived benefits of receiving genomic information. Interviews were audio-recorded, transcribed, and translated.

Results: Fifty individuals completed an interview; 39 were conducted in Spanish. Participants described mixed motivations for pursuing genomic screening. Participants viewed the benefits of genomic screening in relation to not only their personal health but to the health of their families and their communities. Participants tended to have few concerns about genomic screening. Those concerns related to potential loss of privacy, misuses of genomic information, and the possibility of receiving distressing results. Some participants had misunderstandings about the scope of the test and the potential implications of their results. Most felt it was better to know about a genetic predisposition to disease than to remain uninformed. Participants felt that genomic screening was worthwhile.

Discussion: This is one of the first studies to examine the experiences of Latino individuals receiving genomic screening results. Our results suggest that many Latino patients in the US see value in genomic screening and have limited concerns about its potential to cause harm. These results inform ongoing efforts to increase the availability of genomic medicine to underrepresented populations and add to our understanding of sociocultural drivers in the adoption of precision medicine.
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http://dx.doi.org/10.1159/000513219DOI Listing
February 2021

Increasing access to individualized medicine: a matched-cohort study examining Latino participant experiences of genomic screening.

Genet Med 2021 05 26;23(5):934-941. Epub 2021 Jan 26.

Biomedical Ethics Research Program, Mayo Clinic, Rochester, MN, USA.

Purpose: Multiple efforts are underway to increase the inclusion of racial minority participants in genomic research and new forms of individualized medicine. These efforts should include studies that characterize how individuals from minority communities experience genomic medicine in diverse health-care settings and how they integrate genetic knowledge into their understandings of health-care needs.

Methods: As part of a large, multisite genomic sequencing study, we surveyed individuals to assess their decision to pursue genomic risk evaluation. Participants included Latino patients recruited at Mountain Park Health Center, a Federally Qualified Health Center in Phoenix, Arizona, and non-Latino patients recruited at a large academic medical center (Mayo Clinic in Rochester, MN). Both groups agreed to receive individualized genomic risk assessments.

Results: Comparisons between cohorts showed that Latino respondents had lower levels of decisional conflict about pursuing genomic screening but generally scored lower on genetic knowledge. Latino respondents were also more likely to have concerns about the misuse of genomic information, despite both groups having similar views about the value of genomic risk evaluation.

Conclusion: Our results highlight the importance of evaluating sociocultural factors that influence minority patient engagement with genomic medicine in diverse health-care settings.
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http://dx.doi.org/10.1038/s41436-020-01079-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8495890PMC
May 2021

Association between triglycerides, known risk SNVs and conserved rare variation in SLC25A40 in a multi-ancestry cohort.

BMC Med Genomics 2021 01 6;14(1):11. Epub 2021 Jan 6.

Division of Medical Genetics, School of Medicine, University of Washington Medical Center, 1705 NE Pacific St, Box 357720, Seattle, WA, 98195, USA.

Background: Elevated triglycerides (TG) are associated with, and may be causal for, cardiovascular disease (CVD), and co-morbidities such as type II diabetes and metabolic syndrome. Pathogenic variants in APOA5 and APOC3 as well as risk SNVs in other genes [APOE (rs429358, rs7412), APOA1/C3/A4/A5 gene cluster (rs964184), INSR (rs7248104), CETP (rs7205804), GCKR (rs1260326)] have been shown to affect TG levels. Knowledge of genetic causes for elevated TG may lead to early intervention and targeted treatment for CVD. We previously identified linkage and association of a rare, highly conserved missense variant in SLC25A40, rs762174003, with hypertriglyceridemia (HTG) in a single large family, and replicated this association with rare, highly conserved missense variants in a European American and African American sample.

Methods: Here, we analyzed a longitudinal mixed-ancestry cohort (European, African and Asian ancestry, N = 8966) from the Electronic Medical Record and Genomics (eMERGE) Network. We tested associations between median TG and the genes of interest, using linear regression, adjusting for sex, median age, median BMI, and the first two principal components of ancestry.

Results: We replicated the association between TG and APOC3, APOA5, and risk variation at APOE, APOA1/C3/A4/A5 gene cluster, and GCKR. We failed to replicate the association between rare, highly conserved variation at SLC25A40 and TG, as well as for risk variation at INSR and CETP.

Conclusions: Analysis using data from electronic health records presents challenges that need to be overcome. Although large amounts of genotype data is becoming increasingly accessible, usable phenotype data can be challenging to obtain. We were able to replicate known, strong associations, but were unable to replicate moderate associations due to the limited sample size and missing drug information.
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http://dx.doi.org/10.1186/s12920-020-00854-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789246PMC
January 2021

Implementation Science to Increase Adoption of Genomic Medicine: An Urgent Need.

J Pers Med 2020 Dec 29;11(1). Epub 2020 Dec 29.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA.

Advances in genomics have the potential to improve human health [...].
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http://dx.doi.org/10.3390/jpm11010019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824626PMC
December 2020

Risk Factors for Polyvascular Involvement in Patients With Peripheral Artery Disease: A Mendelian Randomization Study.

J Am Heart Assoc 2020 12 8;9(24):e017740. Epub 2020 Dec 8.

Department of Cardiovascular Medicine Mayo Clinic Rochester MN.

Background Atherosclerosis in >1 vascular bed (ie, polyvascular disease), often a feature of peripheral artery disease (PAD), is associated with high morbidity and mortality. We sought to identify risk factors for polyvascular involvement in patients with PAD. Methods and Results We performed 2-sample Mendelian randomization using an inverse-variance-weighted approach, to assess 60 exposures including size and lipid content of atherogenic lipoproteins, blood pressure, glycated hemoglobin, and smoking as causal mediators for polyvascular disease in patients with PAD. Genetic instruments for these exposures were obtained from prior genome-wide association studies. Patients with PAD were from the Mayo Vascular Disease Biorepository, and polyvascular disease (ie, concomitant coronary heart disease, cerebrovascular disease, and/or abdominal aortic aneurysm) was ascertained by validated phenotyping algorithms. Of 3279 patients with PAD, 61% had polyvascular disease. Genetically predicted levels of the lipid content and/or particle measures of very small and small size very low-density lipoprotein, intermediate-density lipoprotein, and large low-density lipoprotein were associated with polyvascular disease: odds ratios (OR) of 1.80 (95% CI, 1.23-2.61), 1.70 (95% CI, 1.17-2.61), and 1.40 (95% CI, 1.09-1.80) per 1 SD increase in genetically determined levels, respectively. Both genetically predicted diastolic and systolic blood pressure were associated with polyvascular disease; OR per 10 mm Hg genetic increase in diastolic and systolic blood pressure were 1.66 (95% CI, 1.19-2.33) and 1.31 (95% CI, 1.07-1.60), respectively. Conclusions Lifetime exposure to increased lipid content and levels of very small and small very low-density lipoprotein, intermediate-density lipoprotein, and large low-density lipoprotein particles as well as elevated blood pressure are associated with polyvascular involvement in patients with PAD. Reduction in levels of such exposures may limit progression of atherosclerosis in patients with PAD.
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http://dx.doi.org/10.1161/JAHA.120.017740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955391PMC
December 2020

Familial Hypercholesterolemia: A Reportable Disorder.

Authors:
Iftikhar J Kullo

Circulation 2020 11 23;142(21):1999-2001. Epub 2020 Nov 23.

Department of Cardiovascular Medicine and the Gonda Vascular Center, Mayo Clinic, Rochester, MN.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687847PMC
November 2020

"They're Not Going to Do Nothing for Me": Research Participants' Attitudes towards Elective Genetic Counseling.

J Pers Med 2020 Sep 24;10(4). Epub 2020 Sep 24.

Biomedical Ethics Research Program, Mayo Clinic, Rochester, MN 55905, USA.

As applications of genomic sequencing have expanded, offering genetic counseling support to all patients is arguably no longer practical. Additionally, whether individuals desire and value genetic counseling services for genomic screening is unclear. We offered elective genetic counseling to 5110 individuals prior to undergoing sequencing and 2310 participants who received neutral results to assess demand. A total of 0.2% of the study participants accessed genetic counseling services prior to sequencing, and 0.3% reached out after receiving neutral results. We later conducted 50 interviews with participants to understand why they did not access these services. Many interviewees did not recall the availability of genetic counseling and were unfamiliar with the profession. Interviewees described not needing counseling before sequencing because they understood the study and felt that they could cope with any result. Counseling was considered equally unnecessary after learning neutral results. Although the participants had questions about their results, they did not feel that speaking with a genetic counselor would be helpful. Genomic screening efforts that employ opt-in models of genetic counseling may need to clarify the potential value of genetic counseling support from the outset and feature genetic counseling services more prominently in program materials.
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http://dx.doi.org/10.3390/jpm10040143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711758PMC
September 2020

Genetic Architecture of Abdominal Aortic Aneurysm in the Million Veteran Program.

Circulation 2020 10 28;142(17):1633-1646. Epub 2020 Sep 28.

Faculty of Medicine and Health Sciences (A.H.S., L.T., M.E.G., K.H., J.B.N.), Norwegian University of Science and Technology, Trondheim, Norway.

Background: Abdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality; however, its genetic determinants remain incompletely defined. In total, 10 previously identified risk loci explain a small fraction of AAA heritability.

Methods: We performed a genome-wide association study in the Million Veteran Program testing ≈18 million DNA sequence variants with AAA (7642 cases and 172 172 controls) in veterans of European ancestry with independent replication in up to 4972 cases and 99 858 controls. We then used mendelian randomization to examine the causal effects of blood pressure on AAA. We examined the association of AAA risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and derived a genome-wide polygenic risk score (PRS) to identify a subset of the population at greater risk for disease.

Results: Through a genome-wide association study, we identified 14 novel loci, bringing the total number of known significant AAA loci to 24. In our mendelian randomization analysis, we demonstrate that a genetic increase of 10 mm Hg in diastolic blood pressure (odds ratio, 1.43 [95% CI, 1.24-1.66]; =1.6×10), as opposed to systolic blood pressure (odds ratio, 1.06 [95% CI, 0.97-1.15]; =0.2), likely has a causal relationship with AAA development. We observed that 19 of 24 AAA risk variants associate with aneurysms in at least 1 other vascular territory. A 29-variant PRS was strongly associated with AAA (odds ratio, 1.26 [95% CI, 1.18-1.36]; =2.7×10 per SD increase in PRS), independent of family history and smoking risk factors (odds ratio, 1.24 [95% CI, 1.14-1.35]; =1.27×10). Using this PRS, we identified a subset of the population with AAA prevalence greater than that observed in screening trials informing current guidelines.

Conclusions: We identify novel AAA genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of AAA independent of family history. Our data suggest that extending current screening guidelines to include testing to identify those with high polygenic AAA risk, once the cost of genotyping becomes comparable with that of screening ultrasound, would significantly increase the yield of current screening at reasonable cost.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580856PMC
October 2020

Loci identified by a genome-wide association study of carotid artery stenosis in the eMERGE network.

Genet Epidemiol 2021 02 22;45(1):4-15. Epub 2020 Sep 22.

Division of Medical Genetics, School of Medicine, University of Washington, Seattle, Washington, USA.

Carotid artery atherosclerotic disease (CAAD) is a risk factor for stroke. We used a genome-wide association (GWAS) approach to discover genetic variants associated with CAAD in participants in the electronic Medical Records and Genomics (eMERGE) Network. We identified adult CAAD cases with unilateral or bilateral carotid artery stenosis and controls without evidence of stenosis from electronic health records at eight eMERGE sites. We performed GWAS with a model adjusting for age, sex, study site, and genetic principal components of ancestry. In eMERGE we found 1793 CAAD cases and 17,958 controls. Two loci reached genome-wide significance, on chr6 in LPA (rs10455872, odds ratio [OR] (95% confidence interval [CI]) = 1.50 (1.30-1.73), p = 2.1 × 10 ) and on chr7, an intergenic single nucleotide variant (SNV; rs6952610, OR (95% CI) = 1.25 (1.16-1.36), p = 4.3 × 10 ). The chr7 association remained significant in the presence of the LPA SNV as a covariate. The LPA SNV was also associated with coronary heart disease (CHD; 4199 cases and 11,679 controls) in this study (OR (95% CI) = 1.27 (1.13-1.43), p = 5 × 10 ) but the chr7 SNV was not (OR (95% CI) = 1.03 (0.97-1.09), p = .37). Both variants replicated in UK Biobank. Elevated lipoprotein(a) concentrations ([Lp(a)]) and LPA variants associated with elevated [Lp(a)] have previously been associated with CAAD and CHD, including rs10455872. With electronic health record phenotypes in eMERGE and UKB, we replicated a previously known association and identified a novel locus associated with CAAD.
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http://dx.doi.org/10.1002/gepi.22360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891640PMC
February 2021

Evaluation of the MC4R gene across eMERGE network identifies many unreported obesity-associated variants.

Int J Obes (Lond) 2021 01 20;45(1):155-169. Epub 2020 Sep 20.

Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA.

Background/objectives: Melanocortin-4 receptor (MC4R) plays an essential role in food intake and energy homeostasis. More than 170 MC4R variants have been described over the past two decades, with conflicting reports regarding the prevalence and phenotypic effects of these variants in diverse cohorts. To determine the frequency of MC4R variants in large cohort of different ancestries, we evaluated the MC4R coding region for 20,537 eMERGE participants with sequencing data plus additional 77,454 independent individuals with genome-wide genotyping data at this locus.

Subjects/methods: The sequencing data were obtained from the eMERGE phase III study, in which multisample variant call format calls have been generated, curated, and annotated. In addition to penetrance estimation using body mass index (BMI) as a binary outcome, GWAS and PheWAS were performed using median BMI in linear regression analyses. All results were adjusted for principal components, age, sex, and sites of genotyping.

Results: Targeted sequencing data of MC4R revealed 125 coding variants in 1839 eMERGE participants including 30 unreported coding variants that were predicted to be functionally damaging. Highly penetrant unreported variants included (L325I, E308K, D298N, S270F, F261L, T248A, D111V, and Y80F) in which seven participants had obesity class III defined as BMI ≥ 40 kg/m. In GWAS analysis, in addition to known risk haplotype upstream of MC4R (best variant rs6567160 (P = 5.36 × 10, Beta = 0.37), a novel rare haplotype was detected which was protective against obesity and encompassed the V103I variant with known gain-of-function properties (P = 6.23 × 10, Beta = -0.62). PheWAS analyses extended this protective effect of V103I to type 2 diabetes, diabetic nephropathy, and chronic renal failure independent of BMI.

Conclusions: MC4R screening in a large eMERGE cohort confirmed many previous findings, extend the MC4R pleotropic effects, and discovered additional MC4R rare alleles that probably contribute to obesity.
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http://dx.doi.org/10.1038/s41366-020-00675-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752751PMC
January 2021
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