A comparative effectiveness study of carotid intervention for long-term stroke prevention in patients with severe asymptomatic stenosis from a large integrated health system.

OBJECTIVE: The results of current prospective trials comparing the effectiveness of carotid endarterectomy (CEA) vs standard medical therapy for long-term stroke prevention in patients with asymptomatic carotid stenosis (ACS) will not be available for several years. In this study, we compared the observed effectiveness of CEA and standard medical therapy vs standard medical therapy alone to prevent ipsilateral stroke in a contemporary cohort of patients with ACS. METHODS: This cohort study was conducted in a large integrated health system in adult subjects with 70% to 99% ACS (no neurologic symptom within 6 months) with no prior ipsilateral carotid artery intervention. Causal inference methods were used to emulate a conceptual randomized trial using data from January 1, 2008, through December 31, 2017, for comparing the event-free survival over 96 months between two treatment strategies: (1) CEA within 12 months from cohort entry vs (2) no CEA (standard medical therapy alone). To account for both baseline and time-dependent confounding, inverse probability weighting estimation was used to derive adjusted hazard ratios, and cumulative risk differences were assessed based on two logistic marginal structural models for counterfactual hazards. Propensity scores were data-adaptively estimated using super learning. The primary outcome was ipsilateral anterior ischemic stroke. RESULTS: The cohort included 3824 eligible patients with ACS (mean age: 73.7 years, 57.9% male, 12.3% active smokers), of whom 1467 underwent CEA in the first year, whereas 2297 never underwent CEA. The median follow-up was 68 months. A total of 1760 participants (46%) died, 445 (12%) were lost to follow-up, and 158 (4%) experienced ipsilateral stroke. The cumulative risk differences for each year of follow-up showed a protective effect of CEA starting in year 2 (risk difference = 1.1%, 95% confidence interval: 0.5%-1.6%) and persisting to year 8 (2.6%, 95% confidence interval: 0.3%-4.8%) compared with patients not receiving CEA. CONCLUSIONS: In this contemporary cohort study of patients with ACS using rigorous analytic methodology, CEA appears to have a small but statistically significant effect on stroke prevention out to 8 years. Further study is needed to appropriately select the subset of patients most likely to benefit from intervention.

The implementation checklist: A pragmatic instrument for accelerating research-to-implementation cycles.

Introduction: Learning health systems require rapid-cycle research and nimble implementation processes to maximize innovation across disparate specialties and operations. Existing detailed research-to-implementation frameworks require extensive time commitments and can be overwhelming for physician-researchers with clinical and operational responsibilities, inhibiting their widespread adoption. The creation of a short, pragmatic checklist to inform implementation processes may substantially improve uptake and implementation efficiency across a variety of health systems. Methods: We conducted a systematic review of existing implementation frameworks to identify core concepts. Utilizing comprehensive stakeholder engagement with 25 operational leaders, embedded physician-researchers, and delivery scientists, concepts were iteratively integrated to create and implement a final concise instrument. Results: A systematic review identified 894 publications describing implementation frameworks, which included 15 systematic reviews. Among these, domains were extracted from three commonly utilized instruments: the Quality Implementation Framework (QIF), the Consolidated Framework for Implementation Research (CFIR), and the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework. Iterative testing and stakeholder engagement revision of a four-page draft implementation document with five domains resulted in a concise, one-page implementation planning instrument to be used at project outset and periodically throughout project implementation planning. The instrument addresses end-user feasibility concerns while retaining the main goals of more complex tools. This instrument was then systematically integrated into projects within the Kaiser Permanente Northern California Delivery Science and Applied Research program to address stakeholder engagement, efficiency, project planning, and operational implementation of study results. Conclusion: A streamlined one-page implementation planning instrument, incorporating core concepts of existing frameworks, provides a pragmatic, robust framework for evidence-based healthcare innovation cycles that is being broadly implemented within a learning health system. These streamlined processes could inform other settings needing a best practice rapid-cycle research-to-implementation tool for large numbers of diverse projects.

Transcriptome-wide association study identifies novel candidate susceptibility genes for migraine.

Genome-wide association studies (GWASs) have identified more than 130 genetic susceptibility loci for migraine; however, how most of these loci impact migraine development is unknown. To identify novel genes associated with migraine and interpret the transcriptional products of those genes, we conducted a transcriptome-wide association study (TWAS). We performed tissue-specific and multi-tissue TWAS analyses to assess associations between imputed gene expression from 53 tissues and migraine susceptibility using FUSION software. Meta-analyzed GWAS summary statistics from 26,052 migraine cases and 487,214 controls, all of European ancestry and from two cohorts (the Kaiser Permanente GERA and the UK Biobank), were used. We evaluated the associations for genes after conditioning on variant-level effects from GWAS, and we tested for colocalization of GWAS migraine-associated loci and expression quantitative trait loci (eQTLs). Across tissue-specific and multi-tissue analyses, we identified 53 genes for which genetically predicted gene expression was associated with migraine after correcting for multiple testing. Of these 53 genes, 10 (ATF5, CNTNAP1, KTN1-AS1, NEIL1, NEK4, NNT, PNKP, RUFY2, TUBG2, and VAT1) did not overlap known migraine-associated loci identified from GWAS. Tissue-specific analysis identified 45 gene-tissue pairs and cardiovascular tissues represented the highest proportion of the Bonferroni-significant gene-tissue pairs (n = 22 [49%]), followed by brain tissues (n = 6 [13%]), and gastrointestinal tissues (n = 4 [9%]). Colocalization analyses provided evidence of shared genetic variants underlying eQTL and GWAS signals in 18 of the gene-tissue pairs (40%). Our TWAS reports novel genes for migraine and highlights the important contribution of brain, cardiovascular, and gastrointestinal tissues in migraine susceptibility.

A Learning Health System Approach to Increasing Human Papillomavirus Immunizations Among Young Adults.

INTRODUCTION Immunization rates against the human papillomavirus (HPV) remain suboptimal in the young adult population. Little is known about the most effective means for encouraging vaccination in this population. METHODS The authors conducted a clinical trial of 3 methods to encourage HPV vaccination in a large Northern California integrated Health Plan. Young adults aged 18-26 with evidence of insufficient HPV vaccination were sent a bulk secure message from the Health Plan (standard outreach); those who did not respond were randomized to no further outreach, a second, personalized secure message from a specific practitioner, or a letter mailed to their home. The primary outcome was receipt of at least 1 HPV vaccine within 3 months following the initial bulk secure message. RESULTS In total, 7718 young adults were randomized. After 3 months, 86 patients (3.5%) who received no additional outreach obtained an immunization, compared with 114 (4.6%) who received the second secure message (p = 0.05) and 126 (5.1%) who received the mailed letter (p = 0.006). DISCUSSION Supplemental mailed or personalized electronic messages increased vaccination beyond no additional intervention, although gains were not clinically meaningful. These findings highlight the need for more successful alternatives to encourage uptake of such preventive health interventions among young adults. The successful conduct of this rapid-cycle, randomized trial showed that such evaluations are feasible, providing actionable data to inform implementation strategies. CONCLUSIONS Further study is needed to identify effective strategies for improving preventive health uptake in this important and underserved population. Rapid-cycle randomized evaluation strategies can provide critical information to focus efforts for achieving this goal.

Acupuncture for chronic low back pain in older adults: Design and protocol for the BackInAction pragmatic clinical trial.

BACKGROUND: Back pain prevalence and burden increase with age; approximately one-third of U.S. adults 65 years of age and older experience lower back pain (LBP). For chronic low back pain (cLBP), typically defined as lasting three months or longer, many treatments for younger adults may be inappropriate for older adults given their greater prevalence of comorbidities with attendant polypharmacy. While acupuncture has been demonstrated to be safe and effective for cLBP in adults overall, few studies of acupuncture have either included or focused on adults ≥65 years old. METHODS: The BackInAction study is a pragmatic, multi-site, three-arm, parallel-groups randomized controlled trial designed to test the effectiveness of acupuncture needling for improving back pain-related disability among 807 older adults ≥65 years old with cLBP. Participants are randomized to standard acupuncture (SA; up to 15 treatment sessions across 12 weeks), enhanced acupuncture (EA; SA during first 12 weeks and up to 6 additional sessions across the following 12 weeks), and usual medical care (UMC) alone. Participants are followed for 12 months with study outcomes assessed monthly with the primary outcome timepoint at 6 months. DISCUSSION: The BackInAction study offers an opportunity to further understand the effectiveness, dose-dependence, and safety of acupuncture in a Medicare population. Additionally, study results may encourage broader adoption of more effective, safer, and more satisfactory options to the continuing over-reliance on opioid- and invasive medical treatments for cLBP among older adults. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04982315. Clinical trial registration date: July 29, 2021.

A population-health approach to characterizing migraine by comorbidity: Results from the Mindfulness and Migraine Cohort Study.

BACKGROUND: The heterogeneity of migraine has been reported extensively, with identified subgroups usually based on symptoms. Grouping individuals with migraine and similar comorbidity profiles has been suggested, however such segmentation methods have not been tested using real-world clinical data. OBJECTIVE: To gain insights into natural groupings of patients with migraine using latent class analysis based on electronic health record-determined comorbidities. METHODS: Retrospective electronic health record data analysis of primary-care patients at Sutter Health, a large open healthcare system in Northern California, USA. We identified migraine patients over a five-year time period (2015-2019) and extracted 29 comorbidities. We then applied latent class analysis to identify comorbidity-based natural subgroups. RESULTS: We identified 95,563 patients with migraine and found seven latent classes, summarized by their predominant comorbidities and population share: fewest comorbidities (61.8%), psychiatric (18.3%), some comorbidities (10.0%), most comorbidities - no cardiovascular (3.6%), vascular (3.1%), autoimmune/joint/pain (2.2%), and most comorbidities (1.0%). We found minimal demographic differences across classes. CONCLUSION: Our study found groupings of migraine patients based on comorbidity that have the potential to be used to guide targeted treatment strategies and the development of new therapies.

Natural History of Asymptomatic Moderate Carotid Artery Stenosis in a Large Community-Based Cohort.

BACKGROUND: Moderate carotid artery stenosis is a poorly defined risk factor for ischemic stroke. As such, practice recommendations are lacking. In this study, we describe the long-term risk of stroke in patients with moderate asymptomatic stenosis in an integrated health care system. METHODS: All adult patients with asymptomatic moderate (50%-69%) internal carotid artery stenosis between 2008 and 2012 were identified, with follow-up through 2017. The primary outcome was acute ischemic stroke attributed to the ipsilateral carotid artery. Stroke rates were calculated using competing risk analysis. Secondary outcomes included disease progression, ipsilateral intervention, and long-term survival. RESULTS: Overall, 11 614 arteries with moderate stenosis in 9803 patients were identified. Mean age was 74.2±9.9 years with 51.4% women. Mean follow-up was 5.1±2.9 years. There were 180 ipsilateral ischemic strokes (1.6%) identified (crude annual risk, 0.31% [95% CI, 0.21%-0.41%]), of which thirty-one (17.2%) underwent subsequent intervention. Controlling for death and intervention as competing risks, the cumulative incidence of stroke was 1.2% (95% CI, 1.0%-1.4%) at 5 years and 2.0% (95% CI, 1.7%-2.4%) at 10 years. Of identified strokes, 50 (27.8%) arteries had progressed to severe stenosis or occlusion. During follow-up, there were 17 029 carotid studies performed in 5951 patients, revealing stenosis progression in 1674 (14.4%) arteries, including 1614 (13.9%) progressing to severe stenosis and 60 (0.5%) to occlusion. The mean time to stenosis progression was 2.6±2.1 years. Carotid intervention occurred in 708 arteries (6.1%). Of these, 66.1% (468/708) had progressed to severe stenosis. The overall mortality rate was 44.5%, with 10.5% of patients lost to follow-up. CONCLUSIONS: In this community-based sample of patients with asymptomatic moderate internal carotid artery stenosis followed for an average of 5 years, the cumulative incidence of stroke is low out to 10 years. Future research is needed to optimize management strategies for this population.

Incidence of Ischemic Stroke in Patients With Asymptomatic Severe Carotid Stenosis Without Surgical Intervention.

Importance: Optimal management of patients with asymptomatic severe carotid stenosis is uncertain, due to advances in medical care and a lack of contemporary data comparing medical and surgical treatment. Objective: To estimate stroke outcomes among patients with medically treated asymptomatic severe carotid stenosis who did not undergo surgical intervention. Design, Setting, and Participants: Retrospective cohort study that included 3737 adult participants with asymptomatic severe (70%-99%) carotid stenosis diagnosed between 2008 and 2012 and no prior intervention or ipsilateral neurologic event in the prior 6 months. Participants received follow-up through 2019, and all were members of an integrated US regional health system serving 4.5 million members. Exposures: Imaging diagnosis of asymptomatic carotid stenosis of 70% to 99%. Main Outcomes and Measures: Occurrence of ipsilateral carotid-related acute ischemic stroke. Censoring occurred with death, disenrollment, or ipsilateral intervention. Results: Among 94 822 patients with qualifying imaging studies, 4230 arteries in 3737 (mean age, 73.8 [SD 9.5 years]; 57.4% male) patients met selection criteria including 2539 arteries in 2314 patients who never received intervention. The mean follow-up in this cohort was 4.1 years (SD 3.6 years). Prior to any intervention, there were 133 ipsilateral strokes with a mean annual stroke rate of 0.9% (95% confidence interval [CI], 0.7%-1.2%). The Kaplan-Meier estimate of ipsilateral stroke by 5 years was 4.7% (95% CI, 3.9%-5.7%). Conclusions and Relevance: In a community-based cohort of patients with asymptomatic severe carotid stenosis who did not undergo surgical intervention, the estimated rate of ipsilateral carotid-related acute ischemic stroke was 4.7% over 5 years. These findings may inform decision-making regarding surgical and medical treatment for patients with asymptomatic severe carotid artery stenosis.

Long-term effectiveness of epidural steroid injections after new episodes of low back pain in older adults.

BACKGROUND: There is limited research on the long-term effectiveness of epidural steroid injections (ESI) in older adults despite the high prevalence of back and leg pain in this age group. We tested the hypotheses that older adults undergoing ESI, compared to patients not receiving ESI: (1) have worse pain, disability and quality of life ('outcomes') pre-ESI, (2) have improved outcomes after ESI and (3) have improved outcomes due to a specific ESI effect. METHODS: We prospectively studied patients ≥65 years old presenting to primary care with new episodes of back pain in three US healthcare systems (BOLD registry). Outcomes were leg and back pain intensity, disability and quality of life, assessed at baseline and 3-, 6-, 12- and 24-month follow-ups. We categorized participants as: (1) ESI within 6 months from the index visit (n = 295); (2) no ESI within 6 months (n = 4809); (3) no ESI within 6 months, propensity-score matched to group 1 (n = 483). We analysed the data using linear regression and Generalized Estimating Equations. RESULTS: Pain intensity, disability and quality of life at baseline were significantly worse at baseline in ESI patients (group 1) than in group 2. The improvement from baseline to 24 months in all outcomes was statistically significant for group 1. However, no statistically significant differences were observed between outcome trajectories for the propensity-score matched groups 1 and 3. CONCLUSIONS: Older adults treated with ESI have long-term improvement. However, the improvement is unlikely the result of a specific ESI effect. SIGNIFICANCE: In this large, two-year, prospective study in older adults with a new episode of low back pain, back pain, leg pain, disability and quality of life improved after epidural steroid injections; however, propensity-score matching revealed that the improvement was unlikely the result of a specific effect of the injections, indicating that epidural steroids are unlikely to provide long-term benefits in older adults with new episodes of back and leg pain.

A refined procedure for esophageal resection using a full minimally invasive approach.

OBJECTIVE: Newer minimally invasive approaches to esophagectomy have brought substantial benefits to esophageal-cancer patients and continue to improve. We report here our experience with a streamlined procedure as part of a comprehensive perioperative-care program that provides additional advances in the continued evolution of this procedure. METHODS: All patients with primary esophageal cancer referred for resection to the Oakland Medical Center of the Kaiser-Permanente Northern California health plan who underwent this approach between January 2013 and August 2018 were included. Operative and clinical outcome variables were extracted from the electronic medical record, operating-room files, and manual chart review. RESULTS: 142 patients underwent the new procedure and care program; 121 (85.2%) were men with mean age of 64.5 years. 127 (89.4%) were adenocarcinoma; 117 (82.4%) were clinical stage III or IVA. 115 (81.0%) required no jejunostomy. Median hospital length-of-stay was 3 days and 8 (5.6%) patients required admission to the intensive care unit. Postoperative complications occurred in 22 (15.5%) patients within 30 days of the procedure. There were no inpatient deaths; one patient (0.7%) died within 30 days following discharge and three additional deaths (2.1%) occurred through 90 days of follow-up. CONCLUSIONS: This approach resulted in excellent clinical outcomes, including short hospital stays with limited need for the intensive care unit, few perioperative complications, and relatively few patients requiring feeding tubes on discharge. This comprehensive approach to esophagectomy is feasible and provides another clinically meaningful advance in the progress of minimally invasive esophagectomy. Further development and dissemination of this method is warranted.

The natural history of large abdominal aortic aneurysms in patients without timely repair.

OBJECTIVE: Contemporary data on the natural history of large abdominal aortic aneurysms (AAAs) in patients undergoing delayed or no repair are lacking. In this study, we examine the impact of large AAA size on the incidence of rupture and mortality. METHODS: From a prospectively maintained aneurysm surveillance registry, patients with an unrepaired, large AAA (≥5.5 cm in men and ≥5.0 cm in women) at baseline (ie, index imaging) or who progressed to a large size from 2003 to 2017 were included, with follow-up through March 2020. Outcomes of interest obtained by manual chart review included rupture (confirmed by imaging/autopsy), probable rupture (timing/findings consistent with rupture without more likely cause of death), repair, reasons for either no or delayed (>1 year after diagnosis of large AAA) repair and total mortality. Cumulative incidence of rupture was calculated using a nonparametric cumulative incidence function, accounting for the competing events of death and aneurysm repair and was stratified by patient sex. RESULTS: Of the 3248 eligible patients (mean age, 83.6 ± 9.1 years; 71.2% male; 78.1% white; and 32.0% current smokers), 1423 (43.8%) had large AAAs at index imaging, and 1825 progressed to large AAAs during the follow-up period, with a mean time to qualifying size of 4.3 ± 3.4 years. In total, 2215 (68%) patients underwent repair, of which 332 were delayed >1 year; 1033 (32%) did not undergo repair. The most common reasons for delayed repair were discrepancy in AAA measurement between surgeon and radiologist (34%) and comorbidity (20%), whereas the most common reasons for no repair were patient preference (48%) and comorbidity (30%). Among patients with delayed repair (mean time to repair, 2.6 ± 1.8 years), nine (2.7%) developed symptomatic aneurysms, and an additional 11 (3.3%) ruptured. Of patients with no repair, 94 (9.1%) ruptured. The 3-year cumulative incidence of rupture was 3.4% for initial AAA size 5.0 to 5.4 cm (women only), 2.2% for 5.5 to 6.0 cm, 6.0% for 6.1 to 7.0 cm, and 18.4% for >7.0 cm. Women with AAA size 6.1 to 7.0 cm had a 3-year cumulative incidence of rupture of 12.8% (95% confidence interval, 7.5%-19.6%) compared with 4.5% (95% confidence interval, 3.0%-6.5%) in men (P = .002). CONCLUSIONS: In this large cohort of AAA registry patients over 17 years, annual rupture rates for large AAAs were lower than previously reported, with possible increased risk in women. Further analyses are ongoing to identify those at increased risk for aneurysm rupture and may provide targeted surveillance regimens and improve patient counseling.

Race-Specific Trends in Prostate Cancer Screening and Presentation before and after the 2012 United States Preventive Services Task Force Statement.

INTRODUCTION: Our goal was to assess temporal changes in the race-specific rates of prostate specific antigen (PSA) screening, prostate biopsy, overall prostate cancer detection and metastatic cancer at presentation among screen-eligible men in Kaiser Permanente Northern California before and after the 2012 United States Preventive Services Task Force Prostate Cancer Screening Statement. METHODS: This was a retrospective study spanning the years 2006 to 2017 in screen-eligible Kaiser Permanente Northern California members (Black men ages 45-69, all other men ages 50-69) with no history of prostate cancer. We compared the race-specific biennial rates of PSA testing, prostate biopsy, overall prostate cancer incidence and metastatic cancer at presentation. RESULTS: A total of 422,664 to 567,660 men per biennial period were evaluated (72% White, 8% Black, 20% Asian). Following the 2012 United States Preventive Services Task Force statement, all races experienced similar declines in screening (22%-25%), biopsy (47%-57%) and overall cancer detection (34%-48%) rates. We found an increase in metastatic rates (39%-105%). CONCLUSIONS: Following the 2012 United States Preventive Services Task Force Statement, in men under the age of 70, PSA screening, biopsy and overall prostate cancer detection rates significantly decreased in a similar fashion across all races, while rates of metastatic disease significantly increased in all races.

Patient, Provider, and Clinic Characteristics Associated with Opioid and Non-Opioid Pain Prescriptions for Patients Receiving Low Back Imaging in Primary Care.

BACKGROUND: To describe characteristics of patients, providers, and clinics associated with opioid or non-opioid pain medication prescribing patterns for patients who received lower spine imaging in primary care clinics. METHODS: In these secondary analyses of the Lumbar Imaging with Reporting of Epidemiology (LIRE) study, a randomized controlled trial conducted in 4 health systems in the United States, we evaluated characteristics associated with receipt of pain medication prescriptions. The outcomes were receipt of prescriptions for opioid or, separately, non-opioid pain medications within 90 days after imaging. Among patients who received opioid or non-opioid prescriptions, we evaluated receipt of multiple prescriptions in the year following imaging. Mixed models were used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Compared with whites, patients identified as Asian (OR, 0.53; 95% CI, 0.51-0.56), Native Hawaiian/Pacific Islander (OR, 0.73; 95% CI, 0.64-0.83), multiracial (OR, 0.84; 95% CI, 0.71-0.98) or Black (OR, 0.92; 95% CI, 0.89-0.96) had significantly reduced odds for receiving prescriptions for opioids within 90 days. Patients identified as Native American/Alaska Native had greater odds for receiving prescriptions for non-opioid pain medications within 90 days (OR, 1.12; 95% CI, 1.01-1.24). Receipt of pain prescriptions 120 days before imaging was strongly predictive of subsequent receipt of pain prescriptions across all categories. CONCLUSIONS: After adjusting for factors that could affect prescribing, the strongest differences observed in pain-medication prescribing were across racial categories and for patients with previous pain prescriptions. Further research is needed to understand these differences and to optimize prescribing.

Expected Organizational Costs for Inserting Prevalence Information Into Lumbar Spine Imaging Reports.

BACKGROUND: Modifying physician behavior to more closely align with guideline-based care can be challenging. Few effective strategies resulting in appropriate spine-related health care have been reported. The Lumbar Imaging With Reporting of Epidemiology (LIRE) intervention did not result in reductions in spine care but did in opioid prescriptions written. OBJECTIVES: To estimate organizational resource needs and costs associated with implementing a pragmatic, decision support-type intervention that inserted age- and modality-matched prevalence information for common lumbar spine imaging findings, using site-based resource use data from the LIRE trial. RESEARCH DESIGN: Time and cost estimation associated with implementing the LIRE intervention in a health organization. SUBJECTS: Providers and patients assessed in the LIRE trial. MEASURES: Expected personnel costs required to implement the LIRE intervention. RESULTS: Annual salaries were converted to daily average per person costs, ranging from $400 to $2,200 per day (base case) for personnel (range: $300-$2,600). Estimated total average cost for implementing LIRE was $5,009 (range: $2,651-$12,020), including conducting pilot testing with providers. Costs associated with a small amount of time for a radiologist (6-12 hours) and imaging-ordering providers (1-8 hours each) account for approximately 75% of the estimated total cost. CONCLUSIONS: The process of implementing an intervention for lumbar spine imaging reports containing age- and modality-appropriate epidemiological benchmarks for common imaging findings required radiologists, imaging-ordering providers, information technology specialists, and limited testing and monitoring. The LIRE intervention seems to be a relatively low-cost, evidence-based, complementary tool that can be easily integrated into the reporting of spine imaging.

New and sex-specific migraine susceptibility loci identified from a multiethnic genome-wide meta-analysis.

Migraine is a common disabling primary headache disorder that is ranked as the most common neurological cause of disability worldwide. Women present with migraine much more frequently than men, but the reasons for this difference are unknown. Migraine heritability is estimated to up to 57%, yet much of the genetic risk remains unaccounted for, especially in non-European ancestry populations. To elucidate the etiology of this common disorder, we conduct a multiethnic genome-wide association meta-analysis of migraine, combining results from the GERA and UK Biobank cohorts, followed by a European-ancestry meta-analysis using public summary statistics. We report 79 loci associated with migraine, of which 45 were novel. Sex-stratified analyses identify three additional novel loci (CPS1, PBRM1, and SLC25A21) specific to women. This large multiethnic migraine study provides important information that may substantially improve our understanding of the etiology of migraine susceptibility.