Publications by authors named "Todd Edwards"

228 Publications

Infant with Clefts Observation Outcomes Instrument (iCOO): A New Outcome for Infants and Young Children with Orofacial Clefts.

Cleft Palate Craniofac J 2021 Sep 13:10556656211040307. Epub 2021 Sep 13.

7284University of Washington, Seattle, WA, USA.

Objective: We evaluated the measurement properties for item and domain scores of the Infant with Clefts Observation Outcomes Instrument (iCOO).

Design: Cross-sectional (before lip surgery) and longitudinal study (preoperative baseline and 2 days and 2 months after lip surgery).

Setting: Three academic craniofacial centers and national online advertisements.

Participants: Primary caregivers with an infant with cleft lip with or without cleft palate (CL  ±  P) scheduled to undergo primary lip repair. There were 133 primary caregivers at baseline, 115 at 2 days postsurgery, and 112 at 2 months postsurgery.

Main Outcome Measure(s): Caregiver observation items ( = 61) and global impression of health and function items ( = 8) across eight health domains.

Results: Mean age at surgery was 6.0 months (range 2.7-11.8 months). Five of eight iCOO domains have scale scores, with Cronbach's alphas ranging from 0.67 to 0.87. Except for the Facial Skin and Mouth domain, iCOO scales had acceptable intraclass correlation coefficients (ICCs) ranging from 0.76 to 0.84. The internal consistency of the Global Impression items across all domains was 0.90 and had acceptable ICCs (range 0.76-0.91). Sixteen out of 20 (nonscale) items had acceptable ICCs (range 0.66-0.96). As anticipated, iCOO scores 2 days postoperatively were generally lower than baseline and scores 2 months postsurgery were consistent with baseline or higher. The iCOO took approximately 10 min to complete.

Conclusions: The iCOO meets measurement standards and may be used for assessing the impact of cleft-related treatments in clinical research and care. More research is needed on its use in various treatment contexts.
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http://dx.doi.org/10.1177/10556656211040307DOI Listing
September 2021

Mapping the genetic architecture of human traits to cell types in the kidney identifies mechanisms of disease and potential treatments.

Nat Genet 2021 09 12;53(9):1322-1333. Epub 2021 Aug 12.

Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA.

The functional interpretation of genome-wide association studies (GWAS) is challenging due to the cell-type-dependent influences of genetic variants. Here, we generated comprehensive maps of expression quantitative trait loci (eQTLs) for 659 microdissected human kidney samples and identified cell-type-eQTLs by mapping interactions between cell type abundances and genotypes. By partitioning heritability using stratified linkage disequilibrium score regression to integrate GWAS with single-cell RNA sequencing and single-nucleus assay for transposase-accessible chromatin with high-throughput sequencing data, we prioritized proximal tubules for kidney function and endothelial cells and distal tubule segments for blood pressure pathogenesis. Bayesian colocalization analysis nominated more than 200 genes for kidney function and hypertension. Our study clarifies the mechanism of commonly used antihypertensive and renal-protective drugs and identifies drug repurposing opportunities for kidney disease.
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http://dx.doi.org/10.1038/s41588-021-00909-9DOI Listing
September 2021

Evidence that geographic variation in genetic ancestry associates with uterine fibroids.

Hum Genet 2021 Oct 23;140(10):1433-1440. Epub 2021 Jul 23.

Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA.

Uterine fibroids disproportionately impact Black women. Evidence suggests Black women have earlier onset and higher cumulative risk. This risk disparity may be due an imbalance of risk alleles in one parental geographic ancestry subgroup relative to others. We investigated ancestry proportions for the 1000 Genomes phase 3 populations clustered into six geographic groups for association with fibroid traits in Black women (n = 583 cases, 797 controls) and White women (n = 1195 cases, 1164 controls). Global ancestry proportions were estimated using ADMIXTURE. Dichotomous (fibroids status and multiple fibroid status) and continuous outcomes (volume and largest dimension) were modeled for association with ancestry proportions using logistic and linear regression adjusting for age. Effect estimates are reported per 10% increase in genetically inferred ancestry proportion. Among Black women, West African (WAFR) ancestry was associated with fibroid risk, East African ancestry was associated with risk of multiple fibroids, Northern European (NEUR) ancestry was protective for multiple fibroids, Southern European ancestry was protective for fibroids and multiple fibroids, and South Asian (SAS) ancestry was positively associated with volume and largest dimension. In White women, NEUR ancestry was protective for fibroids, SAS ancestry was associated with fibroid risk, and WAFR ancestry was positively associated with volume and largest dimension. These results suggest that a proportion of fibroid risk and fibroid trait racial disparities are due to genetic differences between geographic groups. Further investigation at the local ancestry and single variant levels may yield novel insights into disease architecture and genetic mechanisms underlying ethnic disparities in fibroid risk.
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http://dx.doi.org/10.1007/s00439-021-02322-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463481PMC
October 2021

Overview of a Pilot Health-focused Reentry Program for Racial/Ethnic Minority Probationers ages 18 to 26 in Southern California.

Int J Offender Ther Comp Criminol 2021 May 12:306624X211013739. Epub 2021 May 12.

University of California, San Diego School of Medicine, La Jolla, USA.

There is a significant gap in reentry programming that is tailored to the needs of young adults ages 18 to 26 who are in a unique developmental life stage that involves ongoing maturity in their neurobiology, cognitive development, and social and financial transitions to adulthood and independence. This article describes the structure and approach of a 6-month health-focused reentry program designed for racial/ethnic minority young adult (YA) probationers in Southern California. The UCSD RELINK program includes service navigation and an optional psychoeducation health coaching program to build health literacy, problem-solving, and executive functioning skills relevant across multiple life domains. We describe participant characteristics and service needs at intake. Between 2017 and 2019, 122 YA probationers ages 18 to 26 responded to interviewer-administered baseline surveys. Participants needed basic services including housing, nutrition assistance, employment, and educational/vocational training. Depression and anxiety symptoms, Adverse Childhood Events, trauma, and unmet physical and mental health care needs were pervasive. Given the dearth of research on reentry programming for YA, this article documents the approaches taken in this multi-pronged health-focused reentry program to ensure that the program was tailored to YA reentrants' comprehensive needs. These data serve to concretely illustrate the range of needs and how YA reentrants view their own health and social needs in the context of multiple competing demands; such data may be useful for program planners and policymakers seeking to advance service delivery for YA minority reentrants.
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http://dx.doi.org/10.1177/0306624X211013739DOI Listing
May 2021

Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19.

Nat Med 2021 04 9;27(4):668-676. Epub 2021 Apr 9.

Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.

Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 × 10; IFNAR2, P = 9.8 × 10 and IL-10RB, P = 2.3 × 10) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.
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http://dx.doi.org/10.1038/s41591-021-01310-zDOI Listing
April 2021

Development and Content Validity of a Patient-Reported Experience Measure for Home Dialysis.

Clin J Am Soc Nephrol 2021 04 30;16(4):588-598. Epub 2021 Mar 30.

Kidney Research Institute, University of Washington, Seattle, Washington.

Background And Objectives: The population of patients with kidney failure in the United States using home dialysis modalities is growing rapidly. Unlike for in-center hemodialysis, there is no patient-reported experience measure for assessment of patient experience of care for peritoneal dialysis or home hemodialysis. We sought to develop and establish content validity of a patient-reported experience measure for patients undergoing home dialysis using a mixed methods multiple stakeholder approach.

Design, Setting, Participants, & Measurements: We conducted a structured literature review, followed by concept elicitation focus groups and interviews among 65 participants, including 21 patients on home dialysis, 33 home dialysis nurses, three patient care partners, and eight nephrologists. We generated a list of candidate items for possible measure inclusion and conducted a national prioritization exercise among 91 patients on home dialysis and 39 providers using a web-based platform. We drafted the Home Dialysis Care Experience instrument and conducted cognitive debriefing interviews to evaluate item interpretability, order, and structure. We iteratively refined the measure on the basis of interview findings.

Results: The literature review and concept elicitation phases supported 15 domains of home dialysis care experience in six areas: communication and education of patients, concern and helpfulness of the care team, proficiency of the care team, patient-centered care, care coordination, and amenities and environment. Focus groups results showed that domains of highest importance for measure inclusion were patient education and communication, care coordination, and personalization of care. Prioritization exercise results confirmed focus group findings. Cognitive debriefing indicated that the final measure was easily understood and supported content validity.

Conclusions: The Home Dialysis Care Experience instrument is a 26-item patient-reported experience measure for use in peritoneal dialysis and home hemodialysis. The Home Dialysis Care Experience instrument represents the first rigorously developed and content-valid English-language instrument for assessment of patient-reported experience of care in home dialysis.
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http://dx.doi.org/10.2215/CJN.15570920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092066PMC
April 2021

Moral distress of medical family therapists and their physician colleagues during the transition to COVID-19.

J Marital Fam Ther 2021 Apr 9;47(2):289-303. Epub 2021 Mar 9.

University of San Diego, San Diego, CA, USA.

The COVID-19 pandemic has transformed healthcare for both clinicians and patients. This conceptual article uses ideas from the moral distress literature to understand the challenges MedFTs and physicians face during the COVID-19 pandemic. The authors highlight earlier themes from the moral distress literature and share current reflections to illustrate similar challenges. Some clinicians who were already experiencing a rise in burnout due to the mass digitization of healthcare are now facing increased moral distress due to ethical dilemmas, pervasive uncertainty, boundary ambiguity, isolation, and burnout brought about by emerging COVID-19 policies. Fears about personal safety, exposing loved ones, financial concerns, self-doubt, and frustrations with telehealth have contributed to increased moral distress during the COVID-19 pandemic. Building resilience by setting one's personal moral compass can help clinicians avoid the pitfalls of moral distress. Five steps for developing resilience and implications for guiding trainees in developing resilience are discussed.
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http://dx.doi.org/10.1111/jmft.12504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206933PMC
April 2021

Detecting response shift in health-related quality of life measurement among patients with hypertension using structural equation modeling.

Health Qual Life Outcomes 2021 Mar 17;19(1):88. Epub 2021 Mar 17.

Department of Social Medicine of School of Public Health, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, Zhejiang, People's Republic of China.

Background: Outcomes derived from longitudinal self-reported health-related quality of life measures can be confounded by response shift. This study was aimed to detect response shift among patients with hypertension attending a community-based disease management program.

Methods: 240 consecutive consulting or follow-up patients with diagnosed hypertension were recruited. The Short Form 36-item Health Survey was self-administered at 12 community health service stations at baseline and four weeks after attending the program. The 4-step structural equation modeling approach assessed response shift.

Results: Data from 203 (84.6%) patients were eligible for analyses (mean age 65.9 ± 10.8 years, 46.3% female). The results showed uniform recalibration of social functioning ([Formula: see text](1) = 22.98, P < 0.001), and non-uniform recalibration of role limitations due to physical problems ([Formula: see text](1) = 8.84, P = 0.003), and bodily pain ([Formula: see text](1) = 17.41, P < 0.001). The effects of response shift on social functioning were calculated as "small" (effect-size = 0.35), but changed the observed changes from improvement (effect-size = 0.25) to slight deterioration (effect-size = -0.10). After accounting for the response shift effect, the general physical health of participants was improved (effect-size = 0.37), while deterioration (effect-size = -0.21) in the general mental health was also found.

Conclusions: Recalibration existed among patients with hypertension attending the disease management program. The interventions in the program might act as a catalyst that induced the response shift. We conclude that response shift should be considered in hypertension research with longitudinal health-related quality of life data.
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http://dx.doi.org/10.1186/s12955-021-01732-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968327PMC
March 2021

Associations of biogeographic ancestry with hypertension traits.

J Hypertens 2021 04;39(4):633-642

Vanderbilt Genetics Institute, Vanderbilt University.

Objectives: Ethnic disparities in hypertension prevalence are well documented, though the influence of genetic ancestry is unclear. The aim of this study was to evaluate associations of geographic genetic ancestry with hypertension and underlying blood pressure traits.

Methods: We tested genetically inferred ancestry proportions from five 1000 Genomes reference populations (GBR, PEL, YRI, CHB, and LWK) for association with four continuous blood pressure (BP) traits (SBP, DBP, PP, MAP) and the dichotomous outcomes hypertension and apparent treatment-resistant hypertension in 220 495 European American, 59 927 African American, and 21 273 Hispanic American individuals from the Million Veteran Program. Ethnicity stratified results were meta-analyzed to report effect estimates per 10% difference for a given ancestry proportion in all samples.

Results: Percentage GBR was negatively associated with BP (P = 2.13 × 10-19, 7.92 × 10-8, 4.41 × 10-11, and 3.57 × 10-13 for SBP, DBP, PP, and MAP, respectively; coefficient range -0.10 to -0.21 mmHg per 10% increase in ancestry proportion) and was protective against hypertension [P = 2.59 × 10-5, odds ratio (OR) = 0.98] relative to other ancestries. YRI percentage was positively associated with BP (P = 1.63 × 10-23, 1.94 × 10-26, 0.012, and 3.26 × 10-29 for SBP, DBP, PP, and MAP, respectively; coefficient range 0.06-0.32 mmHg per 10% increase in ancestry proportion) and was positively associated with hypertension risk (P = 3.10 × 10-11, OR = 1.04) and apparent treatment-resistant hypertension risk (P = 1.86 × 10-4, OR = 1.04) compared with other ancestries. Percentage PEL was inversely associated with DBP (P = 2.84 × 10-5, beta = -0.11 mmHg per 10% increase in ancestry proportion).

Conclusion: These results demonstrate that risk for BP traits varies significantly by genetic ancestry. Our findings provide insight into the geographic origin of genetic factors underlying hypertension risk and establish that a portion of BP trait ethnic disparities are because of genetic differences between ancestries.
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http://dx.doi.org/10.1097/HJH.0000000000002701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362794PMC
April 2021

Exome-wide evaluation of rare coding variants using electronic health records identifies new gene-phenotype associations.

Nat Med 2021 01 11;27(1):66-72. Epub 2021 Jan 11.

Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA.

The clinical impact of rare loss-of-function variants has yet to be determined for most genes. Integration of DNA sequencing data with electronic health records (EHRs) could enhance our understanding of the contribution of rare genetic variation to human disease. By leveraging 10,900 whole-exome sequences linked to EHR data in the Penn Medicine Biobank, we addressed the association of the cumulative effects of rare predicted loss-of-function variants for each individual gene on human disease on an exome-wide scale, as assessed using a set of diverse EHR phenotypes. After discovering 97 genes with exome-by-phenome-wide significant phenotype associations (P < 10), we replicated 26 of these in the Penn Medicine Biobank, as well as in three other medical biobanks and the population-based UK Biobank. Of these 26 genes, five had associations that have been previously reported and represented positive controls, whereas 21 had phenotype associations not previously reported, among which were genes implicated in glaucoma, aortic ectasia, diabetes mellitus, muscular dystrophy and hearing loss. These findings show the value of aggregating rare predicted loss-of-function variants into 'gene burdens' for identifying new gene-disease associations using EHR phenotypes in a medical biobank. We suggest that application of this approach to even larger numbers of individuals will provide the statistical power required to uncover unexplored relationships between rare genetic variation and disease phenotypes.
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http://dx.doi.org/10.1038/s41591-020-1133-8DOI Listing
January 2021

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Nat Genet 2020 12 23;52(12):1314-1332. Epub 2020 Nov 23.

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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http://dx.doi.org/10.1038/s41588-020-00713-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610439PMC
December 2020

Blunted PTH response to vitamin D insufficiency/deficiency and colorectal neoplasia risk.

Clin Nutr 2021 05 6;40(5):3305-3313. Epub 2020 Nov 6.

Division of Epidemiology, Vanderbilt Ingram Cancer Center, Department of Medicine, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37203, USA. Electronic address:

Background & Aims: In contrast to many observational studies, large-scale randomized trials do not support the protective role of vitamin D for the prevention of colorectal neoplasia. However, in previous studies, individuals with blunted parathyroid hormone (PTH) response to vitamin D insufficiency/deficiency (BPRVID), were not differentiated from those with high PTH response to vitamin D insufficiency/deficiency (HPRVID). Individuals with BPRVID are responsive to magnesium treatment, particularly treatment of magnesium plus vitamin D while those with HPRVID are responsive to vitamin D treatment. We prospectively compared these two distinct groups (i.e. BPRVID and HPRVID) for risk of incident adenoma, metachronous adenoma, and incident colorectal cancer (CRC) METHODS: Three nested case-control studies in the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial.

Results: We found optimal 25(OH)D levels were associated with a significantly reduced risk of CRC, primarily among women. The associations between 25(OH)D and CRC risk significantly differed by PTH levels, particularly among women. Compared to individuals with optimal levels for both 25(OH)D and PTH, all others were at an elevated risk of incident CRC, primarily in women. We found those with BPRVID had 2.56-fold significantly increased risk of CRC compared to 1.65-fold non-significantly increased risk for those with HPRVID. Among women, we observed those with BPRVID had 4.79-6.25-fold significantly increased risks of incident CRC and adenoma whereas those with HPRVID had 3.65-fold significantly increased risk of CRC.

Conclusions: Individuals with BPRVID are at higher risks of incident adenoma and CRC compared to those with HPRVID, particularly among women.
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http://dx.doi.org/10.1016/j.clnu.2020.10.057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099932PMC
May 2021

Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers.

Cancer Epidemiol Biomarkers Prev 2021 01 3;30(1):217-228. Epub 2020 Nov 3.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers.

Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data.

Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers ( = 0.43, = 2.66 × 10). We found seven loci associated with risk for both cancers ( < 2.4 × 10). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified ( < 5 × 10). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation.

Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis.

Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0739DOI Listing
January 2021

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

PheMap: a multi-resource knowledge base for high-throughput phenotyping within electronic health records.

J Am Med Inform Assoc 2020 11;27(11):1675-1687

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Objective: Developing algorithms to extract phenotypes from electronic health records (EHRs) can be challenging and time-consuming. We developed PheMap, a high-throughput phenotyping approach that leverages multiple independent, online resources to streamline the phenotyping process within EHRs.

Materials And Methods: PheMap is a knowledge base of medical concepts with quantified relationships to phenotypes that have been extracted by natural language processing from publicly available resources. PheMap searches EHRs for each phenotype's quantified concepts and uses them to calculate an individual's probability of having this phenotype. We compared PheMap to clinician-validated phenotyping algorithms from the Electronic Medical Records and Genomics (eMERGE) network for type 2 diabetes mellitus (T2DM), dementia, and hypothyroidism using 84 821 individuals from Vanderbilt Univeresity Medical Center's BioVU DNA Biobank. We implemented PheMap-based phenotypes for genome-wide association studies (GWAS) for T2DM, dementia, and hypothyroidism, and phenome-wide association studies (PheWAS) for variants in FTO, HLA-DRB1, and TCF7L2.

Results: In this initial iteration, the PheMap knowledge base contains quantified concepts for 841 disease phenotypes. For T2DM, dementia, and hypothyroidism, the accuracy of the PheMap phenotypes were >97% using a 50% threshold and eMERGE case-control status as a reference standard. In the GWAS analyses, PheMap-derived phenotype probabilities replicated 43 of 51 previously reported disease-associated variants for the 3 phenotypes. For 9 of the 11 top associations, PheMap provided an equivalent or more significant P value than eMERGE-based phenotypes. The PheMap-based PheWAS showed comparable or better performance to a traditional phecode-based PheWAS. PheMap is publicly available online.

Conclusions: PheMap significantly streamlines the process of extracting research-quality phenotype information from EHRs, with comparable or better performance to current phenotyping approaches.
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http://dx.doi.org/10.1093/jamia/ocaa104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751140PMC
November 2020

Equity in Health: Consideration of Race and Ethnicity in Precision Medicine.

Trends Genet 2020 11 22;36(11):807-809. Epub 2020 Jul 22.

Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA; Division of Quantitative Sciences, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address:

The causes for disparities in implementation of precision medicine are complex, due in part to differences in clinical care and a lack of engagement and recruitment of under-represented populations in studies. New tools and large genetic cohorts can change these circumstances and build access to personalized medicine for disadvantaged populations.
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http://dx.doi.org/10.1016/j.tig.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373675PMC
November 2020

Information Loss in Harmonizing Granular Race and Ethnicity Data: Descriptive Study of Standards.

J Med Internet Res 2020 07 20;22(7):e14591. Epub 2020 Jul 20.

Center for Medical Informatics, Yale School of Medicine, New Haven, CT, United States.

Background: Data standards for race and ethnicity have significant implications for health equity research.

Objective: We aim to describe a challenge encountered when working with a multiple-race and ethnicity assessment in the Eastern Caribbean Health Outcomes Research Network (ECHORN), a research collaborative of Barbados, Puerto Rico, Trinidad and Tobago, and the US Virgin Islands.

Methods: We examined the data standards guiding harmonization of race and ethnicity data for multiracial and multiethnic populations, using the Office of Management and Budget (OMB) Statistical Policy Directive No. 15.

Results: Of 1211 participants in the ECHORN cohort study, 901 (74.40%) selected 1 racial category. Of those that selected 1 category, 13.0% (117/901) selected Caribbean; 6.4% (58/901), Puerto Rican or Boricua; and 13.5% (122/901), the mixed or multiracial category. A total of 17.84% (216/1211) of participants selected 2 or more categories, with 15.19% (184/1211) selecting 2 categories and 2.64% (32/1211) selecting 3 or more categories. With aggregation of ECHORN data into OMB categories, 27.91% (338/1211) of the participants can be placed in the "more than one race" category.

Conclusions: This analysis exposes the fundamental informatics challenges that current race and ethnicity data standards present to meaningful collection, organization, and dissemination of granular data about subgroup populations in diverse and marginalized communities. Current standards should reflect the science of measuring race and ethnicity and the need for multidisciplinary teams to improve evolving standards throughout the data life cycle.
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http://dx.doi.org/10.2196/14591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399950PMC
July 2020

Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ancestry meta-analysis.

Nat Genet 2020 07 15;52(7):680-691. Epub 2020 Jun 15.

Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

We investigated type 2 diabetes (T2D) genetic susceptibility via multi-ancestry meta-analysis of 228,499 cases and 1,178,783 controls in the Million Veteran Program (MVP), DIAMANTE, Biobank Japan and other studies. We report 568 associations, including 286 autosomal, 7 X-chromosomal and 25 identified in ancestry-specific analyses that were previously unreported. Transcriptome-wide association analysis detected 3,568 T2D associations with genetically predicted gene expression in 687 novel genes; of these, 54 are known to interact with FDA-approved drugs. A polygenic risk score (PRS) was strongly associated with increased risk of T2D-related retinopathy and modestly associated with chronic kidney disease (CKD), peripheral artery disease (PAD) and neuropathy. We investigated the genetic etiology of T2D-related vascular outcomes in the MVP and observed statistical SNP-T2D interactions at 13 variants, including coronary heart disease (CHD), CKD, PAD and neuropathy. These findings may help to identify potential therapeutic targets for T2D and genomic pathways that link T2D to vascular outcomes.
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http://dx.doi.org/10.1038/s41588-020-0637-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343592PMC
July 2020

Development of an Outcome Measure of Observable Signs of Health and Well-Being in Infants With Orofacial Clefts.

Cleft Palate Craniofac J 2020 11 29;57(11):1266-1279. Epub 2020 May 29.

7284University of Washington, Seattle, WA, USA.

Objective: To develop an outcomes instrument that assesses observations that can be reliably reported by caregivers and can be used to assess health of infants with a cleft lip or cleft lip and cleft palate (CL±P) and impacts of treatments.

Design: Cross-sectional, mixed methods study.

Setting: Caregivers and health-care providers were recruited from 3 academic craniofacial centers and national advertisements. Most interviews were conducted by telephone, and surveys were completed online.

Participants: Caregivers had a child less than 3 years of age with CL±P and spoke either English or Spanish. Health-care providers were members of a cleft team. Caregivers (n = 492) and health-care professionals (n = 75) participated in at least one component of this study.

Main Outcome Measure(s): Caregivers and health-care providers participated in tasks related to instrument development: concept elicitation for items within relevant health domains, prioritization of items, and item review.

Results: We identified 295 observations of infant well-being across 9 health areas. Research staff and specialists evaluated items for clarity, specificity to CL±P, and responsiveness to treatment. Caregivers and health-care providers rated the resulting list of 104 observations and developed the final instrument of 65 items.

Conclusions: In this phase of development of the Infant with Clefts Observation Outcomes (iCOO) instrument, items were developed to collect caregiver observations about indicators of children's health and well-being across multiple domains allowing for psychometric testing, sensitivity to changes associated with treatment, and documentation of the effects of treatment.
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http://dx.doi.org/10.1177/1055665620922105DOI Listing
November 2020

Comparing three approaches for involving patients in research prioritization: a qualitative study of participant experiences.

Res Involv Engagem 2020 1;6:18. Epub 2020 May 1.

2Dept. of Health Services, University of Washington, 1959 NE Pacific St., Seattle, WA 98195 USA.

Background: By participating in priority-setting activities in research, patients and members of the public help ensure that important questions are incorporated into future research agendas. Surveys, focus groups, and online crowdsourcing are increasingly used to obtain input, yet little is known about how they compare for prioritizing research topics. To address this gap, the Study of Methods for Assessing Research Topic Elicitation and pRioritization (SMARTER) evaluated participant satisfaction with the engagement experience across three prioritization activities.

Methods: Respondents from Back pain Outcomes using Longitudinal Data (BOLD), a registry of patients 65 years and older with low back pain (LBP), were randomly assigned to one of three interactive prioritization activities: online crowd-voting, in-person focus groups using nominal group technique, and two rounds of a mailed survey (Delphi). To assess quality of experience, participants completed a brief survey; a subset were subsequently interviewed. We used descriptive statistics to characterize participants, and we analyzed responses to the evaluation using a mixed-methods approach, tabulating responses to Likert-scale questions and using thematic analysis of interviews to explore participant understanding of the activity and perceptions of experience.

Results: The crowd-voting activity had 38 participants, focus groups 39, and the Delphi survey 74. Women outnumbered men in the focus groups and Delphi survey; otherwise, demographics among groups were similar, with participants being predominantly white, non-Hispanic, and college educated. Activities generated similar lists of research priorities, including causes of LBP, improving physician-patient communication, and self-care strategies. The evaluation survey was completed by 123 participants. Of these, 31 across all activities were interviewed about motivations to participate, understanding of activity goals, logistics, clarity of instructions, and the role of patients in research. Focus group participants rated their experience highest, in both the evaluation and interviews.

Conclusion: Common methods for research prioritization yielded similar priorities but differing perceptions of experience. Such comparative studies are rare but important in understanding methods to involve patients and the public in research. Preferences for different methods may vary across stakeholder groups; this warrants future study.

Trial Registration: NICHSR, HSRP20152274. Registered 19 February 2015.
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http://dx.doi.org/10.1186/s40900-020-00196-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195769PMC
May 2020

The polygenic architecture of left ventricular mass mirrors the clinical epidemiology.

Sci Rep 2020 05 5;10(1):7561. Epub 2020 May 5.

Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Left ventricular (LV) mass is a prognostic biomarker for incident heart disease and all-cause mortality. Large-scale genome-wide association studies have identified few SNPs associated with LV mass. We hypothesized that a polygenic discovery approach using LV mass measurements made in a clinical population would identify risk factors and diseases associated with adverse LV remodeling. We developed a polygenic single nucleotide polymorphism-based predictor of LV mass in 7,601 individuals with LV mass measurements made during routine clinical care. We tested for associations between this predictor and 894 clinical diagnoses measured in 58,838 unrelated genotyped individuals. There were 29 clinical phenotypes associated with the LV mass genetic predictor at FDR q < 0.05. Genetically predicted higher LV mass was associated with modifiable cardiac risk factors, diagnoses related to organ dysfunction and conditions associated with abnormal cardiac structure including heart failure and atrial fibrillation. Secondary analyses using polygenic predictors confirmed a significant association between higher LV mass and body mass index and, in men, associations with coronary atherosclerosis and systolic blood pressure. In summary, these analyses show that LV mass-associated genetic variability associates with diagnoses of cardiac diseases and with modifiable risk factors which contribute to these diseases.
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http://dx.doi.org/10.1038/s41598-020-64525-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200691PMC
May 2020

Mendelian Randomization of Circulating Polyunsaturated Fatty Acids and Colorectal Cancer Risk.

Cancer Epidemiol Biomarkers Prev 2020 04 12;29(4):860-870. Epub 2020 Feb 12.

Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.

Background: Results from epidemiologic studies examining polyunsaturated fatty acids (PUFA) and colorectal cancer risk are inconsistent. Mendelian randomization may strengthen causal inference from observational studies. Given their shared metabolic pathway, examining the combined effects of aspirin/NSAID use with PUFAs could help elucidate an association between PUFAs and colorectal cancer risk.

Methods: Information was leveraged from genome-wide association studies (GWAS) regarding PUFA-associated SNPs to create weighted genetic scores (wGS) representing genetically predicted circulating blood PUFAs for 11,016 non-Hispanic white colorectal cancer cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per SD increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on colorectal cancer risk were also examined.

Results: Modest colorectal cancer risk reductions were observed per SD increase in circulating linoleic acid [OR = 0.96; 95% confidence interval (CI) = 0.93-0.98; = 5.2 × 10] and α-linolenic acid (OR = 0.95; 95% CI = 0.92-0.97; = 5.4 × 10), whereas modest increased risks were observed for arachidonic (OR = 1.06; 95% CI = 1.03-1.08; = 3.3 × 10), eicosapentaenoic (OR = 1.04; 95% CI = 1.01-1.07; = 2.5 × 10), and docosapentaenoic acids (OR = 1.03; 95% CI = 1.01-1.06; = 1.2 × 10). Each of these effects was stronger among aspirin/NSAID nonusers in the stratified analyses.

Conclusions: Our study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced colorectal cancer risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased colorectal cancer risk.

Impact: The interaction of PUFAs with aspirin/NSAID use indicates a shared colorectal cancer inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on colorectal cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125012PMC
April 2020

Factors Associated with Health-Related Quality of Life in Children with Intestinal Failure.

J Pediatr 2020 01 4;216:13-18.e1. Epub 2019 Oct 4.

Seattle Children's Hospital, Seattle, WA; University of Washington School of Medicine, Seattle, WA.

Objective: To evaluate disease-specific and age-related factors contributing to health-related quality of life (HRQOL). in children with intestinal failure.

Study Design: A prospective study of HRQOL was performed in a regional intestinal rehabilitation program. Parent-proxy Pediatric Quality of Life Inventory surveys were administered annually to families of 91 children with intestinal failure over a 6-year period. Survey data was stratified by age and compared with pediatric HRQOL data in healthy and chronically ill populations. Linear mixed-effect models using multivariable regression were constructed to identify associations with HRQOL.

Results: A total of 180 surveys were completed by 91 children and their families. HRQOL scores were lowest for children ages 5-7 years (P < .001) and 8-12 years (P < .01), and these changes were primarily related to school dimension scores. In multivariable regression, age of 5 years and older and developmental delay were independently associated with lower HRQOL scores. The trend toward lower HRQOL scores parallels reference data from healthy and chronically ill children, although patients with intestinal failure scored lower than both populations at school age.

Conclusions: Children with intestinal failure experience lower parent-proxy HRQOL scores in the 5-7 and 8-12 year age groups primarily related to school dimension scores. Multicenter data to validate these findings and identify interventions to improve QOL for children with intestinal failure are needed.
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http://dx.doi.org/10.1016/j.jpeds.2019.08.049DOI Listing
January 2020

Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.

Nat Genet 2019 10 2;51(10):1459-1474. Epub 2019 Oct 2.

Department of Neurobiology, Care Sciences and Society, Division of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden.

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.
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http://dx.doi.org/10.1038/s41588-019-0504-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858555PMC
October 2019
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