Citations

Abstract Traditional Hardy–Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in data sets composed of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and to evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence data sets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false-positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently among the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.

Abstract Aims Acute pulmonary disorders are known physical triggers of takotsubo syndrome (TTS). This study aimed to investigate prevalence of acute pulmonary triggers in patients with TTS and their impact on outcomes. Methods and results Patients with TTS were enrolled from the International Takotsubo Registry and screened for triggering factors and comorbidities. Patients were categorized into three groups (acute pulmonary trigger, chronic lung disease, and no lung disease) to compare clinical characteristics and outcomes. Of the 1670 included patients with TTS, 123 (7%) were identified with an acute pulmonary trigger, and 194 (12%) had a known history of chronic lung disease. The incidence of cardiogenic shock was highest in patients with an acute pulmonary trigger compared with those with chronic lung disease or without lung disease (17% vs. 10% vs. 9%, P = 0.017). In-hospital mortality was also higher in patients with an acute pulmonary trigger than in the other two groups, although not significantly (5.7% vs. 1.5% vs. 4.2%, P = 0.13). Survival analysis demonstrated that patients with an acute pulmonary trigger had the worst long-term outcome (P = 0.002). The presence of an acute pulmonary trigger was independently associated with worse long-term mortality (hazard ratio 2.12, 95% confidence interval 1.33–3.38; P = 0.002). Conclusions The present study demonstrates that TTS is related to acute pulmonary triggers in 7% of all TTS patients, which accounts for 21% of patients with physical triggers. The presence of acute pulmonary trigger is associated with a severe in-hospital course and a worse long-term outcome.

Abstract Cognitive resilience is an important modulating factor of cognitive decline in Alzheimer’s disease, but the functional brain mechanisms that support cognitive resilience remain elusive. Given previous findings in normal ageing, we tested the hypothesis that higher segregation of the brain’s connectome into distinct functional networks represents a functional mechanism underlying cognitive resilience in Alzheimer’s disease. Using resting-state functional MRI, we assessed both resting-state functional MRI global system segregation, i.e. the balance of between-network to within-network connectivity, and the alternate index of modularity Q as predictors of cognitive resilience. We performed all analyses in two independent samples for validation: (i) 108 individuals with autosomal dominantly inherited Alzheimer’s disease and 71 non-carrier controls; and (ii) 156 amyloid-PET-positive subjects across the spectrum of sporadic Alzheimer’s disease and 184 amyloid-negative controls. In the autosomal dominant Alzheimer’s disease sample, disease severity was assessed by estimated years from symptom onset. In the sporadic Alzheimer’s sample, disease stage was assessed by temporal lobe tau-PET (i.e. composite across Braak stage I and III regions). In both samples, we tested whether the effect of disease severity on cognition was attenuated at higher levels of functional network segregation. For autosomal dominant Alzheimer’s disease, we found higher functional MRI-assessed system segregation to be associated with an attenuated effect of estimated years from symptom onset on global cognition (P = 0.007). Similarly, for patients with sporadic Alzheimer’s disease, higher functional MRI-assessed system segregation was associated with less decrement in global cognition (P = 0.001) and episodic memory (P = 0.004) per unit increase of temporal lobe tau-PET. Confirmatory analyses using the alternate index of modularity Q revealed consistent results. In conclusion, higher segregation of functional connections into distinct large-scale networks supports cognitive resilience in Alzheimer’s disease.

Abstract Lifestyle interventions are pivotal for successful management of type 2 diabetes (T2D), however, the proportion of people with T2D adhering to physical activity advice has not been thoroughly studied. The purpose of this systematic review was to summarise the evidence on adherence to exercise or physical activity components in lifestyle interventions in those with T2D. We searched MEDLINE EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and Scopus on 12 November 2019. Eligible studies enrolled adults with T2D and reported the proportion of adherence to lifestyle interventions as a primary or secondary outcome. We included 11 studies (nine randomised controlled trials (RCTs) enrolling 1717 patients and two nonrandomised studies enrolling 62 patients). Only one of the studies had low risk of bias. The proportion of participants adhering to physical activity varied from 32% to 100% with a median of 58%. Adherence was higher in interventions using supervised training and lowest in interventions using remote coaching and the adherence rate in observational studies was higher compared to RCTs (92% vs. 55%; p < 0.01). Study duration, risk of bias, or participants' sex, were not associated with adherence to physical activity. The proportion of those with T2D adhering to physical activity interventions for T2D varies widely and most of the included studies had a high risk of bias. These findings have important implications for planning and power analysis of future trials and when counselling patients about lifestyle interventions including physical activity or exercise components.

AbstractIntroductionMachine learning models were used to discover novel disease trajectories for autosomal dominant Alzheimer's disease.MethodsLongitudinal structural magnetic resonance imaging, amyloid positron emission tomography (PET), and fluorodeoxyglucose PET were acquired in 131 mutation carriers and 74 non‐carriers from the Dominantly Inherited Alzheimer Network; the groups were matched for age, education, sex, and apolipoprotein ε4 (APOE ε4). A deep neural network was trained to predict disease progression for each modality. Relief algorithms identified the strongest predictors of mutation status.ResultsThe Relief algorithm identified the caudate, cingulate, and precuneus as the strongest predictors among all modalities. The model yielded accurate results for predicting future Pittsburgh compound B (R2 = 0.95), fluorodeoxyglucose (R2 = 0.93), and atrophy (R2 = 0.95) in mutation carriers compared to non‐carriers.DiscussionResults suggest a sigmoidal trajectory for amyloid, a biphasic response for metabolism, and a gradual decrease in volume, with disease progression primarily in subcortical, middle frontal, and posterior parietal regions.

Background: Lenalidomide combined with rituximab (R2) has shown complimentary clinical activity and is a tolerable regimen in both untreated and relapsed or refractory (R/R) patients with indolent non-Hodgkin lymphoma. Patients with advanced age at diagnosis are considered to be high risk, supporting post-hoc subgroup analyses by age, with a focus on patients aged ≥ 70 years from the MAGNIFY study. Methods: MAGNIFY is a multicenter, phase IIIb trial in patients with R/R follicular lymphoma (FL) grades 1-3b, transformed FL (tFL), marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL; NCT01996865) exploring optimal lenalidomide duration. Lenalidomide 20 mg on days 1-21 of a 28-day cycle + rituximab 375 mg/m2/week cycle 1 and then every 8 weeks starting with cycle 3 (R2) are administered for 12 cycles followed by 1:1 randomization in patients with stable disease, partial response, or complete response/complete response unconfirmed (CR/CRu) to R2 vs rituximab maintenance for 18 months. Data presented here focus on induction R2 in efficacy-evaluable FL grade 1-3a and MZL patients (FL grade 3b, tFL, and MCL not included) receiving ≥ 1 treatment with baseline/postbaseline assessments. The primary end point is progression-free survival (PFS) by 1999 International Working Group criteria. Post-hoc analyses were performed by analyzing data from patients aged ≥ 70 years at time of study entry. Results: As of November 30, 2019, 393 patients have enrolled and 152 (39%) were aged ≥ 70 years. Baseline characteristics including histology, disease status, and prior treatments of patients ≥ 70 and the overall population are shown in the table. Median PFS in the ≥ 70 subgroup was 36.0 months (95% CI, 28.3-NR). Overall response rate and CR/CRu were 75% and 38%, with a median duration of response that was not reached (95% CI, 27.1-NR). Efficacy results for the overall population are shown in the table. In patients ≥ 70 the most common (≥ 20%) any-grade treatment emergent adverse events (TEAEs) were fatigue (44%), neutropenia (41%), diarrhea (34%), constipation (34%), and nausea (27%). Neutropenia (35%) was the only grade 3/4 TEAE occurring in &gt; 10% of patients (febrile neutropenia occurred in 3 patients [2%]). TEAEs led to lenalidomide dose reduction in 69 patients (46%) and discontinuation in 40 patients (26%). Seventy-eight patients ≥ 70 (51%) completed all 12 cycles of induction treatment, and 72 (47%) have entered the maintenance phase. Sixty-one patients ≥ 70 (40%), compared to 35% of patients in overall population, prematurely discontinued both lenalidomide and rituximab, due to TEAEs (n = 26; 17%), progressive disease (n = 15; 10%), patient withdrawal (n = 12; 8%), death (n = 5; 3%), and other reasons (n = 3; 2%). Neutropenia was the only TEAE leading to discontinuation of lenalidomide in more than 2 patients (n = 10; 7%). Conclusions: Similar to findings in the overall population, R2 treatment in advanced-age patients with R/R FL and MZL resulted in encouraging efficacy, and with close attention to dose reduction there is a tolerable safety profile. Table Disclosures Lansigan: BMS Steering Committee for MAGNIFY Program: Membership on an entity's Board of Directors or advisory committees; Spectrum Pharma: Consultancy, Research Funding; BMS: Consultancy; Seattle Genetics: Consultancy. Andorsky:AstraZeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI: Research Funding. Coleman:Novartis Pharmaceuticals: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Boston BIoMedical, Inc.: Research Funding; BeiGene: Research Funding; Acerta: Research Funding; Innocare: Research Funding; ARCUS Biosciences: Research Funding; AstraZeneca Pharmaceuticals, LP (Acerta Pharma BV Trials): Research Funding; AstraZeneca Pharmaceuticals, LP: Research Funding; BMS (Celgene Corporation): Research Funding; Eli Lilly and Company: Research Funding; EMD Serono Research and Development Institute Inc.: Research Funding; Genetech (F. Hoffman-LaRoche Ltd): Research Funding; Hutchinson MediPharma, LTD: Research Funding; Incyte Corporation: Research Funding; Ipsen Group: Research Funding; Karyopharma Therapeutics, Inc.: Research Funding; Klus Pharma, Inc.: Research Funding; MeiPharma, Inc.: Research Funding; Seattle Genetics: Research Funding. Yacoub:Novartis: Honoraria, Speakers Bureau; Agios: Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Dynavax: Current equity holder in publicly-traded company. Melear:AstraZeneca: Speakers Bureau; Janssen: Speakers Bureau. Fanning:Prisma Health: Current Employment; Abbvie: Consultancy; TG Therapeautics: Consultancy; Bristol Myers Squibb: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi Aventis: Speakers Bureau. Kolibaba:Compass Oncology: Ended employment in the past 24 months; Atara Biotech: Consultancy; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sumitomo Dainippon Pharma Oncology: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company; AbbVie: Research Funding; Acerta: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Verastem: Honoraria; Janssen: Research Funding; Novartix: Research Funding. Reynolds:IHA Hematology/Oncology Consultants: Current Employment. Nowakowski:Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Nanostrings: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; MorphoSys: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Kymera: Consultancy; Denovo: Consultancy; Kite: Consultancy; Celgene/BMS: Consultancy, Research Funding. Gharibo:Bayer: Ended employment in the past 24 months; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ahn:BMS: Current Employment, Current equity holder in publicly-traded company. Li:BMS: Current Employment, Current equity holder in publicly-traded company. Rummel:Celgene: Consultancy, Honoraria; Janssen: Honoraria; Amgen GmbH: Honoraria; Roche: Honoraria; Novartis Pharma GmbH: Honoraria. Sharman:Bristol Meyers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Acerta: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; BeiGene: Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding.

Background: Relapse is expected when treating patients with follicular lymphoma (FL) and marginal zone lymphoma (MZL), with a shortened response associated with each relapse. Lenalidomide combined with rituximab (R2) has shown enhanced activity, with a recently reported median progression free-survival (PFS) of 39.4 months in patients with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma, including those with FL and MZL (AUGMENT; J Clin Oncol. 2019;37:1188). Methods: MAGNIFY is a multicenter, phase IIIb trial in patients with R/R FL grades 1-3b, transformed FL (tFL), MZL, or mantle cell lymphoma (MCL; NCT01996865) in which optimal lenalidomide duration is being explored. Patients received 12 cycles of R2 (lenalidomide 20 mg/d, d1-21/28 + rituximab 375 mg/m2 weekly in cycle 1 and then on day 1 of cycles 3, 5, 7, 9, and 11) followed by 1:1 randomization in patients with stable disease, partial response, or complete response/complete response unconfirmed (CR/CRu) to R2 versus rituximab maintenance for 18 months. Data presented here focus on induction R2 in efficacy-evaluable MZL patients compared with the overall population of FL grades 1-3a+MZL (not including FL grade 3b, tFL, or MCL) receiving ≥ 1 treatment with baseline/post-baseline assessments. The primary end point is progression-free survival (PFS) by 1999 International Working Group criteria. Results: As of November 30, 2019, 393 patients with FL grades 1-3a and MZL enrolled; 76 (19%) had MZL. The median age of MZL patients was 68 years (range, 46-90), 68 (89%) had stage III/IV disease, and 72 (95%) had prior rituximab-containing therapy. Overall response rate was 68% with 39% CR/CRu, and median duration of response was 38.6 months (95% CI, 29.4-not reached [NR]). The median PFS was 41.2 months (95% CI, 38.4-NR). Efficacy results for MZL subtypes and the overall population (FL grades 1-3a + MZL) are shown in the table. Forty-two patients (55%) have completed 12 cycles of R2, and 41 (54%) have been randomized and entered maintenance. Twenty-eight patients (37%) prematurely discontinued both lenalidomide and rituximab, primarily due to adverse events (AEs; n = 11; 14%) and progressive disease (n = 6; 8%). The most common (≥ 20%) all-grade AEs were neutropenia (49%), diarrhea (37%), anemia (25%), thrombocytopenia (24%), and constipation (24%). Most common (≥ 10%) grade 3/4 AEs were neutropenia (41%; 1 patient [1%] had febrile neutropenia), thrombocytopenia (13%), and leukopenia (11%). Conclusions: R2 is active with a tolerable safety profile in patients with R/R MZL. The efficacy and safety profile of R2 in MZL patients were similar to results observed in the overall MAGNIFY population. Disclosures Coleman: Seattle Genetics: Research Funding; EMD Serono Research and Development Institute Inc.: Research Funding; Innocare: Research Funding; ARCUS Biosciences: Research Funding; AstraZeneca Pharmaceuticals, LP (Acerta Pharma BV Trials): Research Funding; AstraZeneca Pharmaceuticals, LP: Research Funding; BMS (Celgene Corporation): Research Funding; Eli Lilly and Company: Research Funding; Genetech (F. Hoffman-LaRoche Ltd): Research Funding; Hutchinson MediPharma, LTD: Research Funding; Ipsen Group: Research Funding; Karyopharma Therapeutics, Inc.: Research Funding; Klus Pharma, Inc.: Research Funding; MeiPharma, Inc.: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Novartis Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding; Boston BIoMedical, Inc.: Research Funding; BeiGene: Research Funding; Acerta: Research Funding. Andorsky:CTI: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Research Funding. Yacoub:Roche: Other: Support of parent study and funding of editorial support; Dynavax: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Agios: Honoraria, Speakers Bureau; Novartis: Speakers Bureau. Melear:Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau. Fanning:Takeda: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau; TG Therapeautics: Consultancy; Abbvie: Consultancy; Prisma Health: Current Employment; Sanofi Aventis: Speakers Bureau. Kolibaba:Atara Biotech: Consultancy; Compass Oncology: Ended employment in the past 24 months; Verastem: Honoraria; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Novartix: Research Funding; Janssen: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Acerta: Research Funding; AbbVie: Research Funding; Sumitomo Dainippon Pharma Oncology: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lansigan:BMS: Consultancy; Seattle Genetics: Consultancy; BMS Steering Committee for MAGNIFY Program: Membership on an entity's Board of Directors or advisory committees; Spectrum Pharma: Consultancy, Research Funding. Reynolds:IHA Hematology/Oncology Consultants: Current Employment. Nowakowski:Kymera: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Curis: Consultancy; Kite: Consultancy; MorphoSys: Consultancy, Research Funding; Denovo: Consultancy; Seattle Genetics: Consultancy; Nanostrings: Research Funding; Celgene/BMS: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Gharibo:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; Bayer: Ended employment in the past 24 months. Ahn:BMS: Current Employment, Current equity holder in publicly-traded company. Li:BMS: Current Employment, Current equity holder in publicly-traded company. Rummel:Roche: Honoraria; Amgen GmbH: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Honoraria; Novartis Pharma GmbH: Honoraria. Sharman:BeiGene: Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Acerta: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Abstract Structural grey matter covariance networks provide an individual quantification of morphological patterns in the brain. The network integrity is disrupted in sporadic Alzheimer’s disease, and network properties show associations with the level of amyloid pathology and cognitive decline. Therefore, these network properties might be disease progression markers. However, it remains unclear when and how grey matter network integrity changes with disease progression. We investigated these questions in autosomal dominant Alzheimer’s disease mutation carriers, whose conserved age at dementia onset allows individual staging based upon their estimated years to symptom onset. From the Dominantly Inherited Alzheimer Network observational cohort, we selected T1-weighted MRI scans from 269 mutation carriers and 170 non-carriers (mean age 38 ± 15 years, mean estimated years to symptom onset −9 ± 11), of whom 237 had longitudinal scans with a mean follow-up of 3.0 years. Single-subject grey matter networks were extracted, and we calculated for each individual the network properties which describe the network topology, including the size, clustering, path length and small worldness. We determined at which time point mutation carriers and non-carriers diverged for global and regional grey matter network metrics, both cross-sectionally and for rate of change over time. Based on cross-sectional data, the earliest difference was observed in normalized path length, which was decreased for mutation carriers in the precuneus area at 13 years and on a global level 12 years before estimated symptom onset. Based on longitudinal data, we found the earliest difference between groups on a global level 6 years before symptom onset, with a greater rate of decline of network size for mutation carriers. We further compared grey matter network small worldness with established biomarkers for Alzheimer disease (i.e. amyloid accumulation, cortical thickness, brain metabolism and cognitive function). We found that greater amyloid accumulation at baseline was associated with faster decline of small worldness over time, and decline in grey matter network measures over time was accompanied by decline in brain metabolism, cortical thinning and cognitive decline. In summary, network measures decline in autosomal dominant Alzheimer’s disease, which is alike sporadic Alzheimer’s disease, and the properties show decline over time prior to estimated symptom onset. These data suggest that single-subject networks properties obtained from structural MRI scans form an additional non-invasive tool for understanding the substrate of cognitive decline and measuring progression from preclinical to severe clinical stages of Alzheimer’s disease.

8046 Background: Patients (pts) with relapsed iNHL have limited standard treatment options. The immunomodulatory agent lenalidomide shows enhanced activity with rituximab (ie, R2), which recently reported 39.4-mo median PFS in R/R iNHL pts (AUGMENT; J Clin Oncol. 2019;37:1188). Methods: MAGNIFY is a multicenter, phase IIIb trial in pts with R/R FL gr1-3a, MZL, or MCL (NCT01996865) exploring optimal lenalidomide duration. Lenalidomide 20 mg/d, d1-21/28 + rituximab 375 mg/m2/wk c1 and then q8wk c3+ (R2) are given for 12c followed by 1:1 randomization in pts with SD, PR, or CR to R2 vs rituximab maintenance for 18 mo. Data presented here focus on induction R2 in efficacy-evaluable FL and MZL pts (MCL not included) receiving ≥ 1 treatment with baseline/post-baseline assessments to analyze the primary end point of ORR by 1999 IWG criteria. Results: As of June 16, 2019, 393 pts (81% FL gr1-3a; 19% MZL) were enrolled with a median follow up of 23.7 mo (range, 0.6-57.8) for censored pts (n = 335). Median age was 66 y (range, 35-91), 83% had stage III/IV disease, with a median of 2 prior therapies (95% prior rituximab-containing). ORR was 69% with 40% CR/CRu (Table). Median DOR was 39.0 mo, and median PFS was 40.1 mo. 199 pts (51%) have completed 12c of R2, and 188 (48%) have been randomized and entered maintenance. 139 pts (35%) prematurely discontinued both lenalidomide and rituximab, primarily due to AEs (n = 52, 13%) or PD (n = 45, 11%). Most common all-grade AEs were 48% fatigue, 43% neutropenia, 36% diarrhea, 31% nausea, and 30% constipation. Grade 3/4 AE neutropenia was 36% (9 pts [2%] had febrile neutropenia); all other grade 3/4 AEs occurred in < 7% of pts. Conclusions: R2 is active with a tolerable safety profile in pts with R/R FL and MZL, including rituximab-refractory, double-refractory, and early relapse pts. Clinical trial information: NCT01996865 . [Table: see text]

Background Previous reports have described a leveling off of mortality from premature coronary artery disease (CAD). In recent years, the prevalence of cardiovascular risk factors has increased in rural communities and young adults. Methods and Results We extracted CAD mortality rates from the Centers for Disease Control and Prevention Wide‐Ranging Online Data for Epidemiologic Research (CDC WONDER) database from 1999 to 2017, focusing on mortality from premature CAD (defined as <65 years of age in women) and urban–rural differences. Variations in mortality rates over time, assessed with Joinpoint regression modeling, are expressed as estimated annual percentage change (95% CI) and stratified by urbanization, sex, age, and race. Age‐adjusted mortality rates decreased for women and men. Stratification by urbanization revealed that premature CAD mortality is stagnating among women in rural areas. However, this stagnation conceals a statistically significant increase in CAD mortality rates since 2009 in women aged 55 to 64 years (estimated annual percentage change: +1.4%; 95% CI, +0.3% to +2.5%) and since 1999 in women aged 45 to 54 years (estimated annual percentage change: +0.6%; 95% CI, +0.2% to 1.0%). Since 1999, mortality has been stagnating in the youngest group (aged 35–44 years; estimated annual percentage change: +0.2%; 95% CI, −0.4% to +0.8%). Stratification by race indicated an increase in mortality rates among white rural women. Premature CAD mortality remains consistently higher in the rural versus urban United States, regardless of sex, race, and age group. Conclusions Premature CAD mortality rates have declined over time. However, stratification by sex and urbanization reveals disparities that would otherwise remain concealed: CAD mortality rates have increased among women from rural areas since at least 2009.