Deep phenotyping of dementia in a multi-ethnic cardiovascular cohort: The Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Our understanding of the specific aspects of vascular contributions to dementia remains unclear. OBJECTIVES: We aim to identify the correlates of incident dementia in a multi-ethnic cardiovascular cohort. METHODS: A total of 6806 participants with follow-up data for incident dementia were included. Probable dementia diagnoses were identified using hospitalization discharge diagnoses according to the International Classification of Diseases Codes (ICD). We used Random Forest analyses to identify the correlates of incident dementia and cognitive function from among 198 variables collected at the baseline MESA exam entailing demographic risk factors, medical history, anthropometry, lab biomarkers, electrocardiograms, cardiovascular magnetic resonance imaging, carotid ultrasonography, coronary artery calcium and liver fat content. Death and stroke were considered competing events. RESULTS: Over 14 years of follow-up, 326 dementia events were identified. Beyond age, the top correlates of dementia included coronary artery calcification, high sensitivity troponin, common carotid artery intima to media thickness, NT-proBNP, physical activity, pulse pressure, tumor necrosis factor-α, history of cancer, and liver to spleen attenuation ratio from computed tomography. Correlates of cognitive function included income and physical activity, body size, serum glucose, glomerular filtration rate, measures of carotid artery stiffness, alcohol use, and inflammation indexed as IL-2 and TNF soluble receptors and plasmin-antiplasmin complex. CONCLUSION: In a deeply phenotyped cardiovascular cohort we identified the key correlates of dementia beyond age as subclinical atherosclerosis and myocyte damage, vascular function, inflammation, physical activity, hepatic steatosis, and history of cancer.

Treatment of refractory/relapsed Diamond-Blackfan anaemia with eltrombopag.

Diamond-Blackfan anaemia (DBA) is a rare, inherited bone marrow failure syndrome with a ribosomal defect causing slowed globin chain production with normal haem synthesis, causing an overabundance of reactive iron/haem and erythroid-specific cellular toxicity. Eltrombopag, a non-peptide thrombopoietin receptor agonist, is a potent intracellular iron chelator and induced a robust durable response in an RPS19-mutated DBA patient on another trial. We hypothesized eltrombopag would improve RBC production in DBA patients. We conducted a single-centre, single-arm pilot study (NCT04269889) assessing safety and erythroid response of 6 months of daily, fixed-dose eltrombopag for DBA patients. Fifteen transfusion-dependent (every 3-5 weeks) patients (median age 18 [range 2-56]) were treated. One responder had sustained haemoglobin improvement and >50% reduction in RBC transfusion frequency. Of note, 7/15 (41%) patients required dose reductions or sustained discontinuation of eltrombopag due to asymptomatic thrombocytosis. Despite the low response rate, eltrombopag has now improved erythropoiesis in several patients with DBA with a favourable safety profile. Dosing restrictions due to thrombocytosis may cause insufficient iron chelation to decrease haem production and improve anaemia in most patients. Future work will focus on erythropoiesis dynamics in patients and use of haem synthesis inhibitors without an impact on other haematopoietic lineages.

Venous and Arterial Thrombosis in Patients with VEXAS Syndrome.

VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome, caused by somatic mutations in UBA1, is an autoinflammatory disorder with diverse systemic manifestations. Thrombosis is a prominent clinical feature of VEXAS. The risks factors and frequency of thrombosis in VEXAS are not well described, due to the disease's new discovery and paucity of large databases. We evaluated 119 VEXAS patients for venous and arterial thrombosis and correlated their presence with clinical outcomes and survival. Thrombosis occurred in 49% of patients, mostly venous thromboembolism (VTE; 41%). Almost two thirds of VTE were unprovoked, 41% were recurrent, and 20% occurred despite anticoagulation. The cumulative incidence (CI) of VTE was 17% at 1 year from symptom onset and 40% by 5 years. Cardiac and pulmonary inflammatory manifestations were associated with time to VTE. M41L was positively associated specifically with pulmonary embolism (PE) by univariate (OR: 4.58, CI 1.28-16.21; p=0.02) and multivariate (OR: 16.94, CI 1.99-144.3; p=0.01) logistic regression. The cumulative incidence of arterial thrombosis was 6% at 1 year and 11% at 5 years. The overall survival (OS) of the entire patient cohort at median follow up time of 4.8 years was 88% and there was no difference in survival between patients with or without thrombosis (p=0.8). Patients with VEXAS syndrome are at high risk of VTE; thromboprophylaxis should administered be in high-risk settings unless strongly contraindicated.

Association of Lipoprotein(a) Levels With Myocardial Fibrosis in the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Lipoprotein(a) (Lp[a]) has been identified as an emerging risk factor for adverse cardiovascular (CV) outcomes, including heart failure. However, the connections among Lp(a), myocardial fibrosis (interstitial and replacement), and cardiac remodeling as pathways to CV diseases remains unclear. OBJECTIVES: This study investigated the relationship between Lp(a) levels and myocardial fibrosis by cardiac magnetic resonance (CMR) T1 mapping and late gadolinium enhancement, as well as cardiac remodeling by cine CMR, in the MESA (Multi-Ethnic Study of Atherosclerosis) cohort. METHODS: The study included 2,040 participants with baseline Lp(a) measurements and T1 mapping for interstitial myocardial fibrosis (IMF) evaluation in 2010. Lp(a) was analyzed as a continuous variable (per log unit) and using clinical cutoff values of 30 and 50 mg/dL. Multivariate linear and logistic regression were used to assess the associations of Lp(a) with CMR measures of extracellular volume (ECV fraction [ECV%]), native T1 time, and myocardial scar, as well as parameters of cardiac remodeling, in 2,826 participants. RESULTS: Higher Lp(a) levels were associated with increased ECV% (per log-unit Lp[a]; ß = 0.2%; P = 0.007) and native T1 time (per log-unit Lp[a]; ß = 4%; P < 0.001). Similar relationships were observed between elevated Lp(a) levels and a higher risk of clinically significant IMF defined by prognostic thresholds per log-unit Lp(a) of ECV% (OR: 1.20; 95% CI: 1.04-1.43) and native T1 (OR: 1.2; 95% CI: 1.1-1.4) equal to 30% and 955 ms, respectively. Clinically used Lp(a) cutoffs (30 and 50 mg/dL) were associated with greater prevalence of myocardial scar (OR: 1.85; 95% CI: 1.1-3.2 and OR: 1.9; 95% CI: 1.1-3.4, respectively). Finally, higher Lp(a) levels were associated with left atrial enlargement and dysfunction. CONCLUSIONS: Elevated Lp(a) levels are linked to greater subclinical IMF, increased myocardial scar prevalence, and left atrial remodeling.

Granulocyte transfusions in severe aplastic anemia.

Patients with severe aplastic anemia (SAA) are at high risk for morbidity and mortality due to severe infections. We aimed to characterize the role of granulocyte transfusion (GT) in SAA. Primary outcomes were survival from first GT, including overall survival (OS) at last follow up, survival to discharge, and receipt of HSCT. Secondary outcomes included evaluation of clinical response at 7 and 30 days after GT initiation based on a clinical scoring system incorporating microbiological and radiographic response. Twenty-eight SAA patients underwent 30 GT courses with a per-dose median of 1.28 x 109 granulocyte cells/kilogram (range 0.45-4.52 x 109). OS from initial GT to median last follow up (551 days) was 50%, with 39% (11/28) alive at last follow up. Sixty-four percent (18/28) of all patients survived to hospital discharge. Patients with complete, partial, or stable response at 30 days had significantly improved OS compared to non-responders (p=0.0004). Eighty-six percent (18/21) of patients awaiting HSCT during GT underwent transplant and 62% (13/21) survived to post-HSCT discharge. Sex, type of infection, or percentage of days with absolute neutrophil count > 0.2x109/L during GT course were not predictive of survival (p=0.52, p=0.7, p=0.28). Nine of 28 (32%) patients developed new or increased human leukocyte antigen (HLA) alloimmunization during their GT course. GTs in SAA may impact survival in those with improvement or stabilization of their underlying infection. Alloimmunization can occur and OS in this population remains poor, but GTs may be a useful tool to bridge patients to curative treatment with HSCT.

Thoracic Aortic Volume as a Predictor of Cardiovascular Events: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: It is unclear whether thoracic aortic volume (TAV) is useful for cardiovascular (CV) disease prognosis and risk assessment. PURPOSE: This study evaluated cross-sectional associations of TAV with CV risk factors, and longitudinal association with incident CV events in the multiethnic study of atherosclerosis. STUDY TYPE: Retrospective cohort analysis of prospective data. POPULATION: 1182 participants (69 ± 9 years, 54% female, 37% Caucasian, 18% Chinese, 31% African American, 14% Hispanic, 60% hypertensive, and 20% diabetic) without prior CV disease. FIELD STRENGTH AND SEQUENCES: Axial black-blood turbo spin echo or bright blood steady-state free precession images on 1.5T scanners. ASSESSMENT: TAV was calculated using Simpson's method from axial images, and included the ascending arch and descending segments. Traditional CV risk factors were assessed at the time of MRI. CV outcomes over a 9-year follow-up period were recorded and represented a composite of stroke, stroke death, coronary heart disease (CHD), CHD death, atherosclerotic death, and CVD death. STATISTICAL TESTS: Multivariable linear regression models adjusted for height and weight were used to determine the relationship (ß coefficient) between TAV and CV risk factors. Cox regression models assessed the association of TAV and incident CV events. A P-value of <0.05 was deemed statistically significant. RESULTS: Mean TAV was = 139 ± 41 mL. In multivariable regression, TAV was directly associated with age (ß = 1.6), male gender (ß = 23.9), systolic blood pressure (ß = 0.1), and hypertension medication use (ß = 7.9); and inversely associated with lipid medication use (ß = -5.3) and treated diabetes (ß = -8.9). Compared to Caucasians, Chinese Americans had higher TAV (ß = 11.4), while African Americans had lower TAV (ß = -7.0). Higher TAV was independently associated with incident CV events (HR: 1.057 per 10 mL). CONCLUSION: Greater TAV is associated with incident CV events, increased age, and hypertension in a large multiethnic population while treated diabetes and lipid medication use were associated with lower TAV. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Association between Left Atrial Late Gadolinium Enhancement and Atrial Fibrillation: The Multi-Ethnic Study of Atherosclerosis (MESA).

Purpose: To determine the prevalence and correlates of left atrial (LA) late gadolinium enhancement (LGE) at cardiac MRI and its association with atrial fibrillation (AF) in a population-based sample from the Multi-Ethnic Study of Atherosclerosis (MESA). Materials and Methods: In this secondary post hoc analysis of the MESA cohort (ClinicalTrials.gov no. NCT00005487), participants without AF underwent LGE cardiac MRI at the fifth examination (2010-2012). LA LGE burden was quantified using the image intensity ratio technique on biplane long-axis two-dimensional (2D) LGE images without fat saturation. Survival analysis was performed with log-rank testing and Cox regression. Results: Of 1697 participants (mean age, 67 years ± 9 [SD]; 872 men), 1035 (61%) had LA LGE, and 75 (4.4%) developed AF during follow-up (median, 3.95 years). At univariable analysis, LA LGE was associated with age (ß = .010 [95% CI: .005, .015], P < .001), diastolic blood pressure (ß = .005 [95% CI: .001, .009], P = .02), HbA1c level (ß = .06 [95% CI: .02, .11], P = .009), heart failure (ß = .60 [95% CI: .11, 1.08], P = .02), LA volume (ß = .008 [95% CI: .004, .012], P < .001), and LA function (emptying fraction, LA global longitudinal strain, LA early diastolic peak longitudinal strain rate, and LA late diastolic peak strain rate; all P < .05). After adjusting for the variables in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) AF score, LA LGE independently helped predict incident AF (hazard ratio = 1.46 [95% CI: 1.13, 1.88], P = .003). The highest tertile (LGE > 2%) was twice as likely to develop AF. Conclusion: Although limited by the 2D LGE technique employed, LA LGE was associated with adverse atrial remodeling and helped predict AF in a multiethnic population-based sample.Clinical trial registration no. NCT00005487Keywords: MR Imaging, Cardiac, Epidemiology Supplemental material is available for this article. © RSNA, 2023.

Association between Biomarkers of Inflammation and 10-Year Changes in Aortic Stiffness: The Multi-Ethnic Study of Atherosclerosis.

Background. Chronic inflammation is associated with incident cardiovascular events. We study the association between biomarkers of inflammation and subclinical vascular dysfunction measured as proximal aortic stiffness. Methods. MRI imaging was performed in the Multi-Ethnic Study of Atherosclerosis (MESA) at baseline (2000) and at the 10-year follow-up. Aortic arch pulse wave velocity (PWV) and ascending and descending aorta distensibility (AAD, DAD) were measured in 1223 asymptomatic individuals at both exams. Linear regression was used to study the association of baseline inflammation-C-reactive protein (CRP), interleukin-6 (IL6), and fibrinogen (Fib)-with baseline and 10-year changes in aortic stiffness (PWV, AAD, DAD). Results. The mean age of the participants was 59 ± 9 years, 47.8% of them were men, 32.6% were hypertensive at baseline, and 7.6% were diabetic. At baseline and follow-up, the mean AAD values were, respectively, 1.73 × 10-3 mmHg-1 and 1.57 × 10-3 mmHg-1, the mean DAD values were 2.19 × 10-3 mmHg-1 and 1.99 × 10-3 mmHg-1, and the mean PWV values were 8.10 m/s and 8.99 m/s. At baseline, the AAD (in 10-3 mmHg-1) and DAD (in 10-3 mmHg-1) were inversely associated with CRP (in mg/L) (AAD coeff: -0.047, p-value: 0.011, DAD coeff: -0.068, p-value: <0.001) and IL6 (in pg/mL) (AAD coeff: -0.098, p-value: 0.003, DAD coeff: -0.14, p-value: <0.001) in a univariable analysis but not after adjustment for demographic variables or cardiovascular risk factors. The baseline DAD was inversely associated with Fib (in mg/dL) (coeff: -0.334, p-value: 0.001). The baseline PWV (in m/s) was positively associated with IL6 (in pg/mL) in a univariable analysis (coeff: 0.054, p-value: 0.014). In a longitudinal analysis, the 10-year changes in DAD were inversely associated with CRP, even after adjustment for demographics and risk factors (DAD coeff: -0.08, p-value 0.044). Conclusions. Higher CRP levels at baseline were independently associated with a 10-year increase in aortic stiffness, measured as decreased aortic distensibility.

DYNAMIC RISK PREDICTION TRIGGERED BY INTERMEDIATE EVENTS USING SURVIVAL TREE ENSEMBLES.

With the availability of massive amounts of data from electronic health records and registry databases, incorporating time-varying patient information to improve risk prediction has attracted great attention. To exploit the growing amount of predictor information over time, we develop a unified framework for landmark prediction using survival tree ensembles, where an updated prediction can be performed when new information becomes available. Compared to conventional landmark prediction with fixed landmark times, our methods allow the landmark times to be subject-specific and triggered by an intermediate clinical event. Moreover, the nonparametric approach circumvents the thorny issue of model incompatibility at different landmark times. In our framework, both the longitudinal predictors and the event time outcome are subject to right censoring, and thus existing tree-based approaches cannot be directly applied. To tackle the analytical challenges, we propose a risk-set-based ensemble procedure by averaging martingale estimating equations from individual trees. Extensive simulation studies are conducted to evaluate the performance of our methods. The methods are applied to the Cystic Fibrosis Foundation Patient Registry (CFFPR) data to perform dynamic prediction of lung disease in cystic fibrosis patients and to identify important prognosis factors.

Cardiovascular Interactions of Renin-Angiotensin-Aldosterone System Assessed by Cardiac Magnetic Resonance: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: The effects of the renin-angiotensin-aldosterone system in cardiovascular system have been described based on small studies. The aim of this study was to evaluate the relationship between aldosterone and plasma renin activity (PRA) and cardiovascular structure and function. METHODS: We studied a random sample of Multi-Ethnic Study of Atherosclerosis participants who had aldosterone and PRA blood assays at 2003-2005 and underwent cardiac magnetic resonance at 2010. Participants taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were excluded. RESULTS: The aldosterone group was composed by 615 participants, mean age 61.6 ± 8.9 years, while the renin group was 580 participants, mean age 61.5 ± 8.8 years and both groups had roughly 50% females. In multivariable analysis, 1 SD increment of log-transformed aldosterone level was associated with 0.07 g/m2 higher left ventricle (LV) mass index (P = 0.04) and 0.11 ml/m2 higher left atrium (LA) minimal volume index (P < 0.01). Additionally, higher log-transformed aldosterone was associated with lower LA maximum strain and LA emptying fraction (P < 0.01). Aldosterone levels were not significantly associated with aortic measures. Log-transformed PRA was associated with lower LV end diastolic volume index (ß standardized = 0.08, P = 0.05). PRA levels were not significantly associated with LA and aortic structural or functional differences. CONCLUSIONS: Higher levels of aldosterone and PRA are associated with concentric LV remodeling changes. Moreover, aldosterone was related to deleterious LA remodeling changes.

Statistical considerations for testing automated sphygmomanometers in special patient populations.

The International Standards Organization 81060-2:2018 is the current global Standard for the validation of automated sphygmomanometers. It specifies the requirements for clinical studies on the general population, as well as additional requirements for special populations, which might have physiologic characteristics that affect the accuracy of blood pressure measurements. This paper summarizes the statistical methodology behind the sample size required to test automated sphygmomanometers in these special populations and specifically addresses the pregnant patient population.

Spectrum of clonal hematopoiesis in VEXAS syndrome.

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is caused by somatic mutations in UBA1 (UBA1mut) and characterized by heterogenous systemic autoinflammation and progressive hematologic manifestations, meeting criteria for myelodysplastic syndrome (MDS) and plasma cell dyscrasias. The landscape of myeloid-related gene mutations leading to typical clonal hematopoiesis (CH) in these patients is unknown. Retrospectively, we screened 80 patients with VEXAS for CH in their peripheral blood (PB) and correlated the findings with clinical outcomes in 77 of them. UBA1mut were most common at hot spot p.M41 (median variant allele frequency [VAF] = 75%). Typical CH mutations cooccurred with UBA1mut in 60% of patients, mostly in DNMT3A and TET2, and were not associated with inflammatory or hematologic manifestations. In prospective single-cell proteogenomic sequencing (scDNA), UBA1mut was the dominant clone, present mostly in branched clonal trajectories. Based on integrated bulk and scDNA analyses, clonality in VEXAS followed 2 major patterns: with either typical CH preceding UBA1mut selection in a clone (pattern 1) or occurring as an UBA1mut subclone or in independent clones (pattern 2). VAF in the PB differed markedly between DNMT3A and TET2 clones (median VAF of 25% vs 1%). DNMT3A and TET2 clones associated with hierarchies representing patterns 1 and 2, respectively. Overall survival for all patients was 60% at 10 years. Transfusion-dependent anemia, moderate thrombocytopenia, and typical CH mutations, each correlated with poor outcome. In VEXAS, UBA1mut cells are the primary cause of systemic inflammation and marrow failure, being a new molecularly defined somatic entity associated with MDS. VEXAS-associated MDS is distinct from classical MDS in its presentation and clinical course.

Alemtuzumab in relapsed immune severe aplastic anemia: Long-term results of a phase II study.

Immune severe aplastic anemia (SAA) is characterized by pancytopenia and immune-mediated bone marrow destruction. SAA may be treated with hematopoietic stem cell transplantation (HSCT) or immunosuppressive therapy (IST). However, 30% of patients treated with IST relapse. We previously reported a clinical trial of alemtuzumab in which more than half of 25 relapsed SAA patients (56%) responded hematologically. Here, we present long-term results of a total of 42 patients. Participants with SAA who had previously completed antithymocyte globulin (ATG)-based IST, but had relapsed, were enrolled on this study. Alemtuzumab was administered intravenously (IV) (n = 28) or subcutaneously (SC) (n = 14). The primary endpoint was hematologic response at 6 months. Secondary endpoints included relapse, clonal evolution, and survival. This trial was registered at clinicaltrials.gov (NCT00195624). Patients were enrolled over 9 years, with median follow-up of 6 years. Median age was 32 years, with 57% being female. At 6 months, 18 patients (43%) achieved response; 15 (54%) of those who received IV compared with 3 (21%) who received SC therapy. Six patients (14%) had durable long-term response without need for subsequent AA-directed therapy or HSCT at last follow-up. Nine patients had clonal evolution, with high-risk evolution occurring in 6. Overall survival was 67% at median follow-up of 6 years. Prolonged iatrogenic immunosuppression was observed as long as 2 years after alemtuzumab administration. Alemtuzumab induces responses in relapsed SAA, some of which are durable long-term. However, immunosuppression can persist for years, requiring long-term monitoring.

Accuracy of automated cuff blood pressure monitors in special populations: International Organization for Standardization (ISO) Task Group report and call for research.

OBJECTIVE: Automated cuff blood pressure (BP) devices are widely used for ambulatory, home, and office BP measurement. However, an automated device, which is accurate in the general adult population may be inaccurate in some special populations. A 2018 Collaborative Statement by the US Association for the Advancement of Medical Instrumentation, the European Society of Hypertension, and the International Organization for Standardization (ISO) considered three special populations requiring separate validation (age <3 years, pregnancy, and atrial fibrillation). An ISO Task Group was appointed to identify evidence for additional special populations. METHOD: Evidence on potential special populations was identified from the STRIDE BP database, which performs systematic PubMed searches for published validation studies of automated cuff BP monitors. Devices that passed in a general population, but failed in potential special populations were identified. RESULTS: Of 338 publications (549 validations, 348 devices) in the STRIDE BP database, 29 publications (38 validations, 25 devices) involved 4 potential special populations: (i) age 12-18 years: 3 of 7 devices failed but passed in a general population; (ii) age more than 65 years: 1 of 11 devices failed but passed in a general population; (iii) diabetes type-2: 4 devices (all passed); (iv) chronic kidney disease: 2 of 7 devices failed but passed in a general population. CONCLUSION: Some evidence suggest that the automated cuff BP devices may have different accuracy in adolescents and in patients with chronic kidney disease than in the general population. More research is needed to confirm these findings and investigate other potential special populations.

Association of Incident Cardiovascular Disease With Time Course and Cumulative Exposure to Multiple Risk Factors.

BACKGROUND: The quantitative relationship of incident cardiovascular disease (CVD) to lifetime cumulative risk factor exposure is not well understood. OBJECTIVES: Using CARDIA (Coronary Artery Risk Development in Young Adults) study data, we examined the quantitative associations of cumulative exposure over time to multiple, simultaneously operating risk factors with CVD incidence and the incidence of its components. METHODS: Regression models were developed quantifying the influence of the time course and severity of multiple CVD risk factors, operating simultaneously, on risk of incident CVD. The outcomes were incident CVD and the incidence of its components: coronary heart disease, stroke, and congestive heart failure. RESULTS: Our study included 4,958 asymptomatic adults enrolled in CARDIA from 1985 to 1986 (ages 18 to 30 years) who were followed for 30 years. Risk of incident CVD depends on the time course and severity of a series of independent risk factors, the impact of which is mediated by their effects on individual CVD components after age 40 years. Cumulative exposure (AUC vs time) to low-density lipoprotein cholesterol and triglycerides was independently associated with risk of incident CVD. Of the blood pressure variables, areas under the mean arterial pressure vs time curve and the pulse pressure vs time curve were strongly and independently associated with incident CVD risk. CONCLUSIONS: The quantitative description of the link between risk factors and CVD informs the construction of individualized CVD mitigation strategies, design of primary prevention trials, and assessment of public health impact of risk factor-based interventions.

Analysis of multivariate longitudinal data using dynamic lasso-regularized copula models with application to large pediatric cardiovascular studies.

The National Heart, Lung and Blood Institute Growth and Health Study (NGHS) is a large longitudinal study of childhood health. A main objective of the study is to estimate the joint distributions of cardiovascular risk outcomes at any two time points conditioning on a large number of covariates. Existing multivariate longitudinal methods are not suitable for outcomes at multiple time points. We present a dynamic copula approach for estimating an outcome's joint distributions at two time points given a large number of time-varying covariates. Our models depend on the outcome's time-varying distributions at one time point, the bivariate copula densities and the functional copula parameters. We develop a three-step procedure for variable selection and estimation, which selects the influential covariates using a machine learning procedure based on spline Lasso-regularized least squares, computes the outcome's single-time distribution using splines, and estimates the functional copula parameter of the dynamic copula models. Pointwise confidence intervals are constructed through the resampling-subject bootstrap. We apply our procedure to the NGHS cardiovascular risk data and illustrate the clinical interpretations of the conditional distributions of a set of risk outcomes. We demonstrate the statistical properties of the dynamic models and estimation procedure through a simulation study.

Middle-age high normal serum sodium as a risk factor for accelerated biological aging, chronic diseases, and premature mortality.

BACKGROUND: It is known that some people age faster than others, some people live into old age disease-free, while others develop age-related chronic diseases. With a rapidly aging population and an emerging chronic diseases epidemic, finding mechanisms and implementing preventive measures that could slow down the aging process has become a new challenge for biomedical research and public health. In mice, lifelong water restriction shortens the lifespan and promotes degenerative changes. Here, we test the hypothesis that optimal hydration may slow down the aging process in humans. METHODS: We performed a cohort analysis of data from the Atherosclerosis Risk in Communities study with middle-age enrollment (45-66 years, n = 15,752) and 25 years follow-up. We used serum sodium, as a proxy for hydration habits. To estimate the relative speed of aging, we calculated the biological age (BA) from age-dependent biomarkers and assessed risks of chronic diseases and premature mortality. FINDINGS: The analysis showed that middle age serum sodium >142 mmol/l is associated with a 39% increased risk to develop chronic diseases (hazard ratio [HR] = 1.39, 95% confidence interval [CI]:1.18-1.63) and >144 mmol/l with 21% elevated risk of premature mortality (HR = 1.21, 95% CI:1.02-1.45). People with serum sodium >142 mmol/l had up to 50% higher odds to be older than their chronological age (OR = 1.50, 95% CI:1.14-1.96). A higher BA was associated with an increased risk of chronic diseases (HR = 1.70, 95% CI:1.50-1.93) and premature mortality (HR = 1.59, 95% CI 1.39-1.83). INTERPRETATION: People whose middle-age serum sodium exceeds 142 mmol/l have increased risk to be biologically older, develop chronic diseases and die at younger age. Intervention studies are needed to confirm the link between hydration and aging. FUNDING: This work was funded by Intramural Research program of the National Heart, Lung, and Blood Institute (NHLBI). The ARIC study has been funded in whole or in part with federal funds from the NHLBI; the National Institutes of Health (NIH); and the Department of Health and Human Services.

Multivariate longitudinal data for survival analysis of cardiovascular event prediction in young adults: insights from a comparative explainable study.

BACKGROUND: Multivariate longitudinal data are under-utilized for survival analysis compared to cross-sectional data (CS - data collected once across cohort). Particularly in cardiovascular risk prediction, despite available methods of longitudinal data analysis, the value of longitudinal information has not been established in terms of improved predictive accuracy and clinical applicability. METHODS: We investigated the value of longitudinal data over and above the use of cross-sectional data via 6 distinct modeling strategies from statistics, machine learning, and deep learning that incorporate repeated measures for survival analysis of the time-to-cardiovascular event in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. We then examined and compared the use of model-specific interpretability methods (Random Survival Forest Variable Importance) and model-agnostic methods (SHapley Additive exPlanation (SHAP) and Temporal Importance Model Explanation (TIME)) in cardiovascular risk prediction using the top-performing models. RESULTS: In a cohort of 3539 participants, longitudinal information from 35 variables that were repeatedly collected in 6 exam visits over 15 years improved subsequent long-term (17 years after) risk prediction by up to 8.3% in C-index compared to using baseline data (0.78 vs. 0.72), and up to approximately 4% compared to using the last observed CS data (0.75). Time-varying AUC was also higher in models using longitudinal data (0.86-0.87 at 5 years, 0.79-0.81 at 10 years) than using baseline or last observed CS data (0.80-0.86 at 5 years, 0.73-0.77 at 10 years). Comparative model interpretability analysis revealed the impact of longitudinal variables on model prediction on both the individual and global scales among different modeling strategies, as well as identifying the best time windows and best timing within that window for event prediction. The best strategy to incorporate longitudinal data for accuracy was time series massive feature extraction, and the easiest interpretable strategy was trajectory clustering. CONCLUSION: Our analysis demonstrates the added value of longitudinal data in predictive accuracy and epidemiological utility in cardiovascular risk survival analysis in young adults via a unified, scalable framework that compares model performance and explainability. The framework can be extended to a larger number of variables and other longitudinal modeling methods. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00005130, Registration Date: 26/05/2000.

Periodontal Disease Associated With Interstitial Myocardial Fibrosis: The Multiethnic Study of Atherosclerosis.

Background Periodontitis is a chronic inflammatory disease common among adults. It has been suggested that periodontal disease (PD) may be a contributing risk factor for cardiovascular disease; however, pathways underlying such a relationship require further investigation. Methods and Results A total of 665 men (mean age 68±9 years) and 611 women (mean age 67±9 years) enrolled in the MESA (Multiethnic Study of Atherosclerosis) underwent PD assessment using a 2-item questionnaire at baseline (2000-2002) and had cardiovascular magnetic resonance 10 years later. PD was defined when participants reported either a history of periodontitis or gum disease or lost teeth caused by periodontitis or gum disease. Multivariable linear regression models were constructed to assess the associations of baseline self-reported PD with cardiovascular magnetic resonance-obtained measures of interstitial myocardial fibrosis (IMF), including extracellular volume and native T1 time. Men with a self-reported history of PD had greater extracellular volume percent (ß=0.6%±0.2, P=0.01). This association was independent of age, left ventricular mass, traditional cardiovascular risk factors, and history of myocardial infarction. In a subsequent model, substituting myocardial infarction for coronary artery calcium score, the association of PD with IMF remained significant (ß=0.6%±0.3, P=0.03). In women, a self-reported history of PD was not linked to higher IMF. Importantly, a self-reported history of PD was not found to be associated with myocardial scar independent of sex (odds ratio, 1.01 [95% CI, 0.62-1.65]; P=0.9). Conclusions In a community-based setting, men but not women with a self-reported PD history at baseline were found to be associated with increased measures of IMF. These findings support a plausible link between PD, a proinflammatory condition, and subclinical IMF.

Differential diagnosis of bone marrow failure syndromes guided by machine learning.

The choice to postpone treatment while awaiting genetic testing can result in significant delay in definitive therapies in patients with severe pancytopenia. Conversely, the misdiagnosis of inherited bone marrow failure (BMF) can expose patients to ineffectual and expensive therapies, toxic transplant conditioning regimens, and inappropriate use of an affected family member as a stem cell donor. To predict the likelihood of patients having acquired or inherited BMF, we developed a 2-step data-driven machine-learning model using 25 clinical and laboratory variables typically recorded at the initial clinical encounter. For model development, patients were labeled as having acquired or inherited BMF depending on their genomic data. Data sets were unbiasedly clustered, and an ensemble model was trained with cases from the largest cluster of a training cohort (n = 359) and validated with an independent cohort (n = 127). Cluster A, the largest group, was mostly immune or inherited aplastic anemia, whereas cluster B comprised underrepresented BMF phenotypes and was not included in the next step of data modeling because of a small sample size. The ensemble cluster A-specific model was accurate (89%) to predict BMF etiology, correctly predicting inherited and likely immune BMF in 79% and 92% of cases, respectively. Our model represents a practical guide for BMF diagnosis and highlights the importance of clinical and laboratory variables in the initial evaluation, particularly telomere length. Our tool can be potentially used by general hematologists and health care providers not specialized in BMF, and in under-resourced centers, to prioritize patients for genetic testing or for expeditious treatment.