Browsing by Author "Akushevich, Igor"

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    A Systematic Review of Conceptual Frameworks of Medical Complexity and New Model Development.
    (J Gen Intern Med, 2016-03) Zullig, Leah L; Whitson, Heather E; Hastings, Susan N; Beadles, Chris; Kravchenko, Julia; Akushevich, Igor; Maciejewski, Matthew L
    BACKGROUND: Patient complexity is often operationalized by counting multiple chronic conditions (MCC) without considering contextual factors that can affect patient risk for adverse outcomes. OBJECTIVE: Our objective was to develop a conceptual model of complexity addressing gaps identified in a review of published conceptual models. DATA SOURCES: We searched for English-language MEDLINE papers published between 1 January 2004 and 16 January 2014. Two reviewers independently evaluated abstracts and all authors contributed to the development of the conceptual model in an iterative process. RESULTS: From 1606 identified abstracts, six conceptual models were selected. One additional model was identified through reference review. Each model had strengths, but several constructs were not fully considered: 1) contextual factors; 2) dynamics of complexity; 3) patients' preferences; 4) acute health shocks; and 5) resilience. Our Cycle of Complexity model illustrates relationships between acute shocks and medical events, healthcare access and utilization, workload and capacity, and patient preferences in the context of interpersonal, organizational, and community factors. CONCLUSIONS/IMPLICATIONS: This model may inform studies on the etiology of and changes in complexity, the relationship between complexity and patient outcomes, and intervention development to improve modifiable elements of complex patients.
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    Age patterns of incidence of geriatric disease in the U.S. elderly population: Medicare-based analysis.
    (J Am Geriatr Soc, 2012-02) Akushevich, Igor; Kravchenko, Julia; Ukraintseva, Svetlana; Arbeev, Konstantin; Yashin, Anatoliy I
    OBJECTIVES: To use the Medicare Files of Service Use (MFSU) to evaluate patterns in the incidence of aging-related diseases in the U.S. elderly population. DESIGN: Age-specific incidence rates of 19 aging-related diseases were evaluated using the National Long Term Care Survey (NLTCS) and the Surveillance, Epidemiology, and End Results (SEER) Registry data, both linked to MFSU (NLTCS-M and SEER-M, respectively), using an algorithm developed for individual date at onset evaluation. SETTING: A random sample from the entire U.S. elderly population (Medicare beneficiaries) was used in NLTCS, and the SEER Registry data covers 26% of the U.S. population. PARTICIPANTS: Thirty-four thousand seventy-seven individuals from NLTCS-M and 2,154,598 from SEER-M. MEASUREMENTS: Individual medical histories were reconstructed using information on diagnoses coded in MFSU, dates of medical services and procedures, and Medicare enrollment and disenrollment. RESULTS: The majority of diseases (e.g., prostate cancer, asthma, and diabetes mellitus) had a monotonic decline (or decline after a short period of increase) in incidence with age. A monotonic increase in incidence with age with a subsequent leveling off and decline was observed for myocardial infarction, stroke, heart failure, ulcer, and Alzheimer's disease. An inverted U-shaped age pattern was detected for lung and colon carcinomas, Parkinson's disease, and renal failure. The results obtained from the NLTCS-M and SEER-M were in agreement (excluding an excess for circulatory diseases in the NLTCS-M). A sensitivity analysis proved the stability of the incidence rates evaluated. CONCLUSION: The developed computational approaches applied to the nationally representative Medicare-based data sets allow reconstruction of age patterns of disease incidence in the U.S. elderly population at the national level with unprecedented statistical accuracy and stability with respect to systematic biases.
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    Age trajectories of physiological indices in relation to healthy life course.
    (Mech Ageing Dev, 2011-03) Arbeev, Konstantin G; Ukraintseva, Svetlana V; Akushevich, Igor; Kulminski, Alexander M; Arbeeva, Liubov S; Akushevich, Lucy; Culminskaya, Irina V; Yashin, Anatoliy I
    We analysed relationship between the risk of onset of "unhealthy life" (defined as the onset of cancer, cardiovascular diseases, or diabetes) and longitudinal changes in body mass index, diastolic blood pressure, hematocrit, pulse pressure, pulse rate, and serum cholesterol in the Framingham Heart Study (Original Cohort) using the stochastic process model of human mortality and aging. The analyses demonstrate how decline in resistance to stresses and adaptive capacity accompanying human aging can be evaluated from longitudinal data. We showed how these components of the aging process, as well as deviation of the trajectories of physiological indices from those minimising the risk at respective ages, can lead to an increase in the risk of onset of unhealthy life with age. The results indicate the presence of substantial gender difference in aging related decline in stress resistance and adaptive capacity, which can contribute to differences in the shape of the sex-specific patterns of incidence rates of aging related diseases.
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    Assessing tilavonemab efficacy in early Alzheimer's disease via longitudinal item response theory modeling
    (Alzheimer's & Dementia: Translational Research & Clinical Interventions, 2024-04) Zhou, Xiaoxiao; Zou, Haotian; Lutz, Michael W; Arbeev, Konstantin; Akushevich, Igor; Yashin, Anatoli; Welsh-Bohmer, Kathleen A; Luo, Sheng
    AbstractINTRODUCTIONAlzheimer's disease (AD) is a neurodegenerative disorder characterized by declines in cognitive and functional severities. This research utilized the Clinical Dementia Rating (CDR) to assess the influence of tilavonemab on these deteriorations.METHODSLongitudinal Item Response Theory (IRT) models were employed to analyze CDR domains in early‐stage AD patients. Both unidimensional and multidimensional models were contrasted to elucidate the trajectories of cognitive and functional severities.RESULTSWe observed significant temporal increases in both cognitive and functional severities, with the cognitive severity deteriorating at a quicker rate. Tilavonemab did not demonstrate a statistically significant effect on the progression in either severity. Furthermore, a significant positive association was identified between the baselines and progression rates of both severities.DISCUSSIONWhile tilavonemab failed to mitigate impairment progression, our multidimensional IRT analysis illuminated the interconnected progression of cognitive and functional declines in AD, suggesting a comprehensive perspective on disease trajectories.Highlights Utilized longitudinal Item Response Theory (IRT) models to analyze the Clinical Dementia Rating (CDR) domains in early‐stage Alzheimer's disease (AD) patients, comparing unidimensional and multidimensional models. Observed significant temporal increases in both cognitive and functional severities, with cognitive severity deteriorating at a faster rate, while tilavonemab showed no statistically significant effect on either domain's progression. Found a significant positive association between the baseline severities and their progression rates, indicating interconnected progression patterns of cognitive and functional declines in AD. Introduced the application of multidimensional longitudinal IRT models to provide a comprehensive perspective on the trajectories of cognitive and functional severities in early AD, suggesting new avenues for future research including the inclusion of time‐dependent random effects and data‐driven IRT models.
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    Benefit of adjuvant chemotherapy after resection of stage II (T1-2N1M0) non-small cell lung cancer in elderly patients.
    (Ann Surg Oncol, 2015-02) Berry, Mark F; Coleman, Brooke K; Curtis, Lesley H; Worni, Mathias; D'Amico, Thomas A; Akushevich, Igor
    BACKGROUND: We evaluated the use and efficacy of adjuvant chemotherapy after resection of T1-2N1M0 non-small cell lung cancer (NSCLC) in elderly patients. METHODS: Factors associated with the use of adjuvant chemotherapy in patients older than 65 years of age who underwent surgical resection of T1-2N1M0 NSCLC without induction chemotherapy or radiation in the Surveillance, Epidemiology, and End Results-Medicare database from 1992 to 2006 were assessed using a multivariable logistic regression model that included treatment, patient, tumor, and census tract characteristics. Overall survival (OS) was analyzed using the Kaplan-Meier approach and inverse probability weight-adjusted Cox proportional hazard models. RESULTS: Overall, 2,781 patients who underwent surgical resection as the initial treatment for T1-2N1M0 NSCLC and survived at least 31 days after surgery were identified, with adjuvant chemotherapy given to 784 patients (28.2 %). Factors that predicted adjuvant chemotherapy use were younger age and higher T status. The 5-year OS was significantly better for patients who received adjuvant chemotherapy compared with patients not given adjuvant chemotherapy: 35.8 % (95 % confidence interval [CI] 31.9-39.6) vs. 28.0 % (95 % CI 25.9-30.0) (p = 0.008). In the inverse probability weight-adjusted Cox proportional hazard regression model, adjuvant chemotherapy use predicted significantly improved survival (hazard ratio 0.84; 95 % CI 0.76-0.92; p = 0.0002). CONCLUSIONS: Adjuvant chemotherapy after resection of T1-2N1M0 NSCLC is associated with significantly improved survival in patients older than 65 years. These data can be used to provide elderly patients with realistic expectations of the potential benefits when considering adjuvant chemotherapy in this setting.
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    Biodemographic Analyses of Longitudinal Data on Aging, Health, and Longevity: Recent Advances and Future Perspectives.
    (Adv Geriatr, 2017-06-02) Arbeev, Konstantin G; Akushevich, Igor; Kulminski, Alexander M; Ukraintseva, Svetlana V; Yashin, Anatoliy I
    Biodemography became one of the most innovative and fastest growing areas in demography. This progress is fueled by the growing variability and amount of relevant data available for analyses as well as by methodological developments allowing for addressing new research questions using new approaches that can better utilize the potential of these data. In this review paper, we summarize recent methodological advances in biodemography and their diverse practical applications. Three major topics are covered: (1) computational approaches to reconstruction of age patterns of incidence of geriatric diseases and other characteristics such as recovery rates at the population level using Medicare claims data; (2) methodological advances in genetic and genomic biodemography and applications to research on genetic determinants of longevity and health; and (3) biodemographic models for joint analyses of time-to-event data and longitudinal measurements of biomarkers collected in longitudinal studies on aging. We discuss how such data and methodology can be used in a comprehensive prediction model for joint analyses of incomplete datasets that take into account the wide spectrum of factors affecting health and mortality transitions including genetic factors and hidden mechanisms of aging-related changes in physiological variables in their dynamic connection with health and survival.
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    Breast cancer as heterogeneous disease: contributing factors and carcinogenesis mechanisms.
    (Breast Cancer Res Treat, 2011-07) Kravchenko, Julia; Akushevich, Igor; Seewaldt, Victoria L; Abernethy, Amy P; Lyerly, H Kim
    The observed bimodal patterns of breast cancer incidence in the U.S. suggested that breast cancer may be viewed as more than one biological entity. We studied the factors potentially contributing to this phenomenon, specifically focusing on how disease heterogeneity could be linked to breast carcinogenesis mechanisms. Using empirical analyses and population-based biologically motivated modeling, age-specific patterns of incidence of ductal and lobular breast carcinomas from the SEER registry (1990-2003) were analyzed for heterogeneity and characteristics of carcinogenesis, stratified by race, stage, grade, and estrogen (ER)/progesterone (PR) receptor status. The heterogeneity of breast carcinoma age patterns decreased after stratification by grade, especially for grade I and III tumors. Stratification by ER/PR status further reduced the heterogeneity, especially for ER(+)/PR(-) and ER(-)/(-) tumors; however, the residual heterogeneity was still observed. The number of rate-limiting events of carcinogenesis and the latency of ductal and lobular carcinomas differed, decreasing from grade I to III, with poorly differentiated tumors associated with the least number of carcinogenesis stages and the shortest latency. Tumor grades play important role in bimodal incidence of breast carcinoma and have distinct mechanisms of carcinogenesis. Race and cancer subtype could play modifying role. ER/PR status contributes to the observed heterogeneity, but is subdominant to tumor grade. Further studies on sources of "remaining" heterogeneity of population with breast cancer (such as genetic/epigenetic characteristics) are necessary. The results of this study could suggest stratification rather than unification of breast cancer prevention strategies, risk assessment, and treatment.
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    Cancer Risk and Behavioral Factors, Comorbidities, and Functional Status in the US Elderly Population.
    (ISRN Oncol, 2011) Akushevich, Igor; Kravchenko, Julia; Akushevich, Lucy; Ukraintseva, Svetlana; Arbeev, Konstantin; Yashin, Anatoliy
    About 80% of all cancers are diagnosed in the elderly and up to 75% of cancers are associated with behavioral factors. An approach to estimate the contribution of various measurable factors, including behavior/lifestyle, to cancer risk in the US elderly population is presented. The nationally representative National Long-Term Care Survey (NLTCS) data were used for measuring functional status and behavioral factors in the US elderly population (65+), and Medicare Claims files linked to each person from the NLTCS were used for estimating cancer incidence. The associations (i.e., relative risks) of selected factors with risks of breast, prostate, lung and colon cancers were evaluated and discussed. Behavioral risk factors significantly affected cancer risks in the US elderly. The most influential of potentially preventable risk factors can be detected with this approach using NLTCS-Medicare linked dataset and for further deeper analyses employing other datasets with detailed risk factors description.
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    Cardiovascular comorbidities and survival of lung cancer patients: Medicare data based analysis.
    (Lung Cancer, 2017-06-05) Kravchenko, Julia; Berry, Mark; Arbeev, Konstantin; Lyerly, H Kim; Yashin, Anatoly; Akushevich, Igor
    OBJECTIVES: To evaluate the role of cardiovascular disease (CVD) comorbidity in survival of patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: The impact of seven CVDs (at the time of NSCLC diagnosis and during subsequent follow-up) on overall survival was studied for NSCLC patients aged 65+ years using the Surveillance, Epidemiology, and End Results data linked to the U.S. Medicare data, cancer stage- and treatment-specific. Cox regression was applied to evaluate death hazard ratios of CVDs in univariable and multivariable analyses (controlling by age, TNM statuses, and 78 non-CVD comorbidities) and to investigate the effects of 128 different combinations of CVDs on patients' survival. RESULTS: Overall, 95,167 patients with stage I (n=29,836, 31.4%), II (n=5133, 5.4%), IIIA (n=11,884, 12.5%), IIIB (n=18,020, 18.9%), and IV (n=30,294, 31.8%) NSCLC were selected. Most CVDs increased the risk of death for stages I-IIIB patients, but did not significantly impact survival of stage IV patients. The worse survival of patients was associated with comorbid heart failure, myocardial infarction, and cardiac arrhythmias that occurred during a period of follow-up: HRs up to 1.85 (p<0.001), 1.96 (p<0.05), and 1.67 (p<0.001), respectively, varying by stage and treatment. The presence of hyperlipidemia at baseline (HR down to 0.71, p<0.05) was associated with better prognosis. Having multiple co-existing CVDs significantly increased mortality for all treatments, especially for stages I and II patients treated with surgery (HRs up to 2.89, p<0.05) and stages I-IIIB patients treated with chemotherapy (HRs up to 2.59, p<0.001) and chemotherapy and radiotherapy (HRs up to 2.20, p<0.001). CONCLUSION: CVDs impact the survival of NSCLC patients, particularly when multiple co-existing CVDs are present; the impacts vary by stage and treatment. This data should be considered in improving cancer treatment selection process for such potentially challenging patients as the elderly NSCLC patients with CVD comorbidities.
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    Causal effects of time-dependent treatments in older patients with non-small cell lung cancer.
    (PLoS One, 2015) Akushevich, Igor; Arbeev, Konstantin; Kravchenko, Julia; Berry, Mark
    BACKGROUND: Treatment selection for elderly patients with lung cancer must balance the benefits of curative/life-prolonging therapy and the risks of increased mortality due to comorbidities. Lung cancer trials generally exclude patients with comorbidities and current treatment guidelines do not specifically consider comorbidities, so treatment decisions are usually made on subjective individual-case basis. METHODS: Impacts of surgery, radiation, and chemotherapy mono-treatment as well as combined chemo/radiation on one-year overall survival (compared to no-treatment) are studied for stage-specific lung cancer in 65+ y.o. patients. Methods of causal inference such as propensity score with inverse probability weighting (IPW) for time-independent and marginal structural model (MSM) for time-dependent treatments are applied to SEER-Medicare data considering the presence of comorbid diseases. RESULTS: 122,822 patients with stage I (26.8%), II (4.5%), IIIa (11.5%), IIIb (19.9%), and IV (37.4%) lung cancer were selected. Younger age, smaller tumor size, and fewer baseline comorbidities predict better survival. Impacts of radio- and chemotherapy increased and impact of surgery decreased with more advanced cancer stages. The effects of all therapies became weaker after adjustment for selection bias, however, the changes in the effects were minor likely due to the weak selection bias or incompleteness of the list of predictors that impacted treatment choice. MSM provides more realistic estimates of treatment effects than the IPW approach for time-independent treatment. CONCLUSIONS: Causal inference methods provide substantive results on treatment choice and survival of older lung cancer patients with realistic expectations of potential benefits of specific treatments. Applications of these models to specific subsets of patients can aid in the development of practical guidelines that help optimize lung cancer treatment based on individual patient characteristics.
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    Circulatory Diseases in the U.S. Elderly in the Linked National Long-Term Care Survey-Medicare Database: Population-Based Analysis of Incidence, Comorbidity, and Disability.
    (Res Aging, 2013-07) Akushevich, Igor; Kravchenko, Julia; Ukraintseva, Svetlana; Arbeev, Konstantin; Yashin, Anatoli I
    Incidence rates of acute coronary heart disease (ACHD; including myocardial infarction and angina pectoris), stroke, and heart failure (HF) were studied for their age, disability, and comorbidity patterns in the U.S. elderly population using the National Long Term Care Survey (NLTCS) data linked to Medicare records for 1991-2005. Incidence rates increased with age with a decrease in the oldest old (stroke and HF) or were stable at all ages (ACHD). For all diseases, incidence rates were lower among institutionalized individuals and higher in individuals with higher comorbidity indices. The results could be used for understanding currently debated effects of biomedical research, screening, and therapeutic innovations on changes in disease incidence with advancing age as well as for projecting future Medicare costs.
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    Discordance in Grading Methods of Aortic Stenosis by Pre-Cardiopulmonary Bypass Transesophageal Echocardiography.
    (Anesth Analg, 2016-04) Whitener, George; McKenzie, Jeff; Akushevich, Igor; White, William D; Dhakal, Ishwori B; Nicoara, Alina; Swaminathan, Madhav
    BACKGROUND: Current guidelines define severe aortic valve stenosis (AS) as an aortic valve area (AVA) ≤1.0 cm by the continuity equation and mean gradient (ΔPm) ≥ 40 mm Hg. However, these measurements can be discordant when classifying AS severity. Approximately one-third of patients with normal ejection fraction and severe AS by AVA have nonsevere AS by ΔPm when measured by preoperative transthoracic echocardiography (TTE). Given the use of positive pressure ventilation and general anesthesia in the pre-cardiopulmonary bypass (pre-CPB) period, we hypothesized that discordance between ΔPm and AVA during pre-CPB transesophageal echocardiography (TEE) would be higher than previously reported by TTE. METHODS: We retrospectively examined pre-CPB TEE data for patients who had aortic valve replacement, with or without coronary artery bypass grafting, from 2000 to 2012. Patients were excluded if they had ejection fraction <55%, emergency surgery, repeat sternotomy, moderate or severe mitral regurgitation, or severe aortic regurgitation. Only patients with both pre-CPB AVA and ΔPm measurements were included. Patients were grouped according to severity (mild, moderate, and severe) by AVA or ΔPm. Discordance was defined as disagreement between severities based on either parameter. RESULTS: A total of 277 patients met inclusion criteria. There were 227 patients with AVA ≤ 1.0 cm. The proportion of these patients with a ΔPm < 40 mm Hg was 54% (95% confidence interval, 47%-61%). The rate of discordance was significantly higher than the rate (37%; P < 0.001) found in previously reported analyses using TTE. Of the patients with a ΔPm ≥ 40 mm Hg, only 8% (n = 9/113) had a discordant AVA. In contrast, of the patients with ΔPm < 40 mm Hg, 80% (n = 131/164) had a discordant AVA. CONCLUSIONS: We confirmed our hypothesis that grading AS by ΔPm and AVA during pre-CPB TEE exhibits higher discordance than reported for TTE by others. It remains unclear whether these discrepancies reflect the effect of general anesthesia, imaging modality (TTE versus TEE) differences, inaccuracies in AS grading cutoffs when applied to pre-CPB TEE, or selection bias of the surgical population.
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    Does surgery improve outcomes for esophageal squamous cell carcinoma? An analysis using the surveillance epidemiology and end results registry from 1998 to 2008.
    (J Am Coll Surg, 2012-11) Worni, Mathias; Martin, Jeremiah; Gloor, Beat; Pietrobon, Ricardo; D'Amico, Thomas A; Akushevich, Igor; Berry, Mark F
    BACKGROUND: We examined survival associated with locally advanced esophageal squamous cell cancer (SCC) to evaluate if treatment without surgery could be considered adequate. STUDY DESIGN: Patients in the Surveillance, Epidemiology and End Results Registry (SEER) registry with stage II-III SCC of the mid or distal esophagus from 1998-2008 were grouped by treatment with definitive radiation versus esophagectomy with or without radiation. Information on chemotherapy is not recorded in SEER. Tumor stage was defined as first clinical tumor stage in case of neo-adjuvant therapy and pathological report if no neo-adjuvant therapy was performed. Cancer-specific (CSS) and overall survival (OS) were analyzed using the Kaplan-Meier approach and propensity-score adjusted Cox proportional hazard models. RESULTS: Of the 2,431 patients analyzed, there were 844 stage IIA (34.7%), 428 stage IIB (17.6%), 1,159 stage III (47.7%) patients. Most were treated with definitive radiation (n = 1,426, 58.7%). Of the 1,005 (41.3%) patients who underwent surgery, 369 (36.7%) had preoperative radiation, 160 (15.9%) had postoperative radiation, and 476 (47.4%) had no radiation. Five-year survival was 17.9% for all patients, and 22.1%, 18.5%, and 14.5% for stages IIA, IIB, and stage III, respectively. Compared to treatment that included surgery, definitive radiation alone predicted worse propensity-score adjusted survival for all patients (CSS Hazard Ratio [HR] 1.48, p < 0.001; OS HR 1.46, p < 0.001) and for stage IIA, IIB, and III patients individually (all p values ≤ 0.01). Compared to surgery alone, surgery with radiation predicted improved survival for stage III patients (CSS HR 0.62, p = 0.001, OS HR 0.62, p < 0.001) but not stage IIA or IIB (all p values > 0.18). CONCLUSIONS: Esophagectomy is associated with improved survival for patients with locally advanced SCC and should be considered as an integral component of the treatment algorithm if feasible.
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    Effect of the APOE Polymorphism and Age Trajectories of Physiological Variables on Mortality: Application of Genetic Stochastic Process Model of Aging.
    (Scientifica (Cairo), 2012) Arbeev, Konstantin G; Ukraintseva, Svetlana V; Kulminski, Alexander M; Akushevich, Igor; Arbeeva, Liubov S; Culminskaya, Irina V; Wu, Deqing; Yashin, Anatoliy I
    We evaluated effects of the APOE polymorphism (carriers versus noncarriers of the e4 allele) and age trajectories of total cholesterol (CH) and diastolic blood pressure (DBP) on mortality risk in the Framingham Heart Study (original cohort). We found that long-lived carriers and noncarriers have different average age trajectories and long-lived individuals have consistently higher levels and less steep declines at old ages compared to short-lived individuals. We applied the stochastic process model of aging aimed at joint analyses of genetic and nongenetic subsamples of longitudinal data and estimated different aging-related characteristics for carriers and noncarriers which otherwise cannot be evaluated from data. We found that such characteristics differ in carriers and noncarriers: (1) carriers have better adaptive capacity than noncarriers in case of CH, whereas for DBP the opposite situation is observed; (2) mean allostatic trajectories are higher in carriers and they differ from "optimal" trajectories minimizing mortality risk; (3) noncarriers have lower baseline mortality rates at younger ages but they increase faster than those for carriers resulting in intersection at the oldest ages. Such observations strongly indicate the presence of a genetic component in respective aging-related mechanisms. Such differences may contribute to patterns of allele- and sex-specific mortality rates.
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    Epidemiology of geographic disparities in heart failure among US older adults: a Medicare-based analysis.
    (BMC public health, 2022-07) Yu, Bin; Akushevich, Igor; Yashkin, Arseniy P; Yashin, Anatoliy I; Lyerly, H Kim; Kravchenko, Julia

    Background

    There are prominent geographic disparities in the life expectancy (LE) of older US adults between the states with the highest (leading states) and lowest (lagging states) LE and their causes remain poorly understood. Heart failure (HF) has been proposed as a major contributor to these disparities. This study aims to investigate geographic disparities in HF outcomes between the leading and lagging states.

    Methods

    The study was a secondary data analysis of HF outcomes in older US adults aged 65+, using Center for Disease Control and Prevention sponsored Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) database and a nationally representative 5% sample of Medicare beneficiaries over 2000-2017. Empiric estimates of death certificate-based mortality from HF as underlying cause of death (CBM-UCD)/multiple cause of death (CBM-MCD); HF incidence-based mortality (IBM); HF incidence, prevalence, and survival were compared between the leading and lagging states. Cox regression was used to investigate the effect of residence in the lagging states on HF incidence and survival.

    Results

    Between 2000 and 2017, HF mortality rates (per 100,000) were higher in the lagging states (CBM-UCD: 188.5-248.6; CBM-MCD: 749.4-965.9; IBM: 2656.0-2978.4) than that in the leading states (CBM-UCD: 79.4-95.6; CBM-MCD: 441.4-574.1; IBM: 1839.5-2138.1). Compared to their leading counterparts, lagging states had higher HF incidence (2.9-3.9% vs. 2.2-2.9%), prevalence (15.6-17.2% vs. 11.3-13.0%), and pre-existing prevalence at age 65 (5.3-7.3% vs. 2.8-4.1%). The most recent rates of one- (77.1% vs. 80.4%), three- (59.0% vs. 60.7%) and five-year (45.8% vs. 49.8%) survival were lower in the lagging states. A greater risk of HF incidence (Adjusted Hazards Ratio, AHR [95%CI]: 1.29 [1.29-1.30]) and death after HF diagnosis (AHR: 1.12 [1.11-1.13]) was observed for populations in the lagging states. The study also observed recent increases in CBMs and HF incidence, and declines in HF prevalence, prevalence at age 65 and survival with a decade-long plateau stage in IBM in both leading and lagging states.

    Conclusion

    There are substantial geographic disparities in HF mortality, incidence, prevalence, and survival across the U.S.: HF incidence, prevalence at age 65 (age of Medicare enrollment), and survival of patients with HF contributed most to these disparities. The geographic disparities and the recent increase in incidence and decline in survival underscore the importance of HF prevention strategies.
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    Evaluating the number of stages in development of squamous cell and adenocarcinomas across cancer sites using human population-based cancer modeling.
    (PLoS One, 2012) Kravchenko, Julia; Akushevich, Igor; Abernethy, Amy P; Lyerly, H Kim
    BACKGROUND: Adenocarcinomas (ACs) and squamous cell carcinomas (SCCs) differ by clinical and molecular characteristics. We evaluated the characteristics of carcinogenesis by modeling the age patterns of incidence rates of ACs and SCCs of various organs to test whether these characteristics differed between cancer subtypes. METHODOLOGY/PRINCIPAL FINDINGS: Histotype-specific incidence rates of 14 ACs and 12 SCCs from the SEER Registry (1973-2003) were analyzed by fitting several biologically motivated models to observed age patterns. A frailty model with the Weibull baseline was applied to each age pattern to provide the best fit for the majority of cancers. For each cancer, model parameters describing the underlying mechanisms of carcinogenesis including the number of stages occurring during an individual's life and leading to cancer (m-stages) were estimated. For sensitivity analysis, the age-period-cohort model was incorporated into the carcinogenesis model to test the stability of the estimates. For the majority of studied cancers, the numbers of m-stages were similar within each group (i.e., AC and SCC). When cancers of the same organs were compared (i.e., lung, esophagus, and cervix uteri), the number of m-stages were more strongly associated with the AC/SCC subtype than with the organ: 9.79±0.09, 9.93±0.19 and 8.80±0.10 for lung, esophagus, and cervical ACs, compared to 11.41±0.10, 12.86±0.34 and 12.01±0.51 for SCCs of the respective organs (p<0.05 between subtypes). Most SCCs had more than ten m-stages while ACs had fewer than ten m-stages. The sensitivity analyses of the model parameters demonstrated the stability of the obtained estimates. CONCLUSIONS/SIGNIFICANCE: A model containing parameters capable of representing the number of stages of cancer development occurring during individual's life was applied to the large population data on incidence of ACs and SCCs. The model revealed that the number of m-stages differed by cancer subtype being more strongly associated with ACs/SCCs histotype than with organ/site.
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    Evaluation of genotype-specific survival using joint analysis of genetic and non-genetic subsamples of longitudinal data.
    (Biogerontology, 2011-04) Arbeev, Konstantin G; Ukraintseva, Svetlana V; Arbeeva, Liubov S; Akushevich, Igor; Kulminski, Alexander M; Yashin, Anatoliy I
    Small sample size of genetic data is often a limiting factor for desirable accuracy of estimated genetic effects on age-specific risks and survival. Longitudinal non-genetic data containing information on survival or disease onsets of study participants for whom the genetic data were not collected may provide an additional "reserve" for increasing the accuracy of respective estimates. We present a novel method for joint analyses of "genetic" (covering individuals for whom both genetic information and mortality/morbidity data are available) and "non-genetic" (covering individuals for whom only mortality/morbidity data were collected) subsamples of longitudinal data. Our simulation studies show substantial increase in the accuracy of estimates in such joint analyses compared to analyses based on genetic subsample alone. Application of this method to analysis of the effect of common apolipoprotein E (APOE) polymorphism on survival using combined genetic and non-genetic subsamples of the Framingham Heart Study original cohort data showed that female, but not male, carriers of the APOE e4 allele have significantly worse survival than non-carriers, whereas empirical analyses did not produce any significant results for either sex.
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    Exploring the association between melanoma and glioma risks.
    (Ann Epidemiol, 2014-06) Scarbrough, Peter M; Akushevich, Igor; Wrensch, Margaret; Il'yasova, Dora
    PURPOSE: Gliomas are one of the most fatal malignancies, with largely unknown etiology. This study examines a possible connection between glioma and melanoma, which might provide insight into gliomas' etiology. METHODS: Using data provided by the Surveillance, Epidemiology, and End Results program from 1992 to 2009, a cohort was constructed to determine the incidence rates of glioma among those who had a prior diagnosis of invasive melanoma. Glioma rates in those with prior melanoma were compared with those in the general population. RESULTS: The incidence rate of all gliomas was greater among melanoma cases than in the general population: 10.46 versus 6.13 cases per 100,000 person-years, standardized incidence ratios = 1.42 (1.22-1.62). The female excess rate was slightly greater (42%) than that among males (29%). Sensitivity analyses did not reveal evidence that radiation treatment of melanoma is responsible for the detected gap in the rates of gliomas. CONCLUSIONS: Our analysis documented increased risk of glioma among melanoma patients. Because no common environmental risk factors are identified for glioma and melanoma, it is hypothesized that a common genetic predisposition may be responsible for the detected association.
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    Genetic Structures of Population Cohorts Change with Increasing Age: Implications for Genetic Analyses of Human aging and Life Span.
    (Ann Gerontol Geriatr Res, 2017-06-02) Yashin, Anatoliy I; Wu, Deqing; Arbeev, Konstantin G; Arbeeva, Liubov S; Akushevich, Igor; Kulminski, Alexander; Culminskaya, Irina; Stallard, Eric; Ukraintseva, Svetlana V
    BACKGROUND: Correcting for the potential effects of population stratification is an important issue in genome wide association studies (GWAS) of complex traits. Principal component analysis (PCA) of the genetic structure of the population under study with subsequent incorporation of the first several principal components (PCs) in the GWAS regression model is often used for this purpose. PROBLEM: For longevity related traits such a correction may negatively affect the accuracy of genetic analyses. This is because PCs may capture genetic structure induced by mortality selection processes in genetically heterogeneous populations. DATA AND METHODS: We used the Framingham Heart Study data on life span and on individual genetic background to construct two sets of PCs. One was constructed to separate population stratification due to differences in ancestry from that induced by mortality selection. The other was constructed using genetic data on individuals of different ages without attempting to separate the ancestry effects from the mortality selection effects. The GWASs of human life span were performed using the first 20 PCs from each of the selected sets to control for possible population stratification. RESULTS: The results indicated that the GWAS that used the PC set separating population stratification induced by mortality selection from differences in ancestry produced stronger genetic signals than the GWAS that used PCs without such separation. CONCLUSION: The quality of genetic estimates in GWAS can be improved when changes in genetic structure caused by mortality selection are taken into account in controlling for possible effects of population stratification.
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    Genetics of aging, health, and survival: dynamic regulation of human longevity related traits.
    (Front Genet, 2015) Yashin, Anatoliy I; Wu, Deqing; Arbeeva, Liubov S; Arbeev, Konstantin G; Kulminski, Alexander M; Akushevich, Igor; Kovtun, Mikhail; Culminskaya, Irina; Stallard, Eric; Li, Miaozhu; Ukraintseva, Svetlana V
    BACKGROUND: The roles of genetic factors in human longevity would be better understood if one can use more efficient methods in genetic analyses and investigate pleiotropic effects of genetic variants on aging and health related traits. DATA AND METHODS: We used EMMAX software with modified correction for population stratification to perform genome wide association studies (GWAS) of female lifespan from the original FHS cohort. The male data from the original FHS cohort and male and female data combined from the offspring FHS cohort were used to confirm findings. We evaluated pleiotropic effects of selected genetic variants as well as gene-smoking interactions on health and aging related traits. Then we reviewed current knowledge on functional properties of genes related to detected variants. RESULTS: The eight SNPs with genome-wide significant variants were negatively associated with lifespan in both males and females. After additional QC, two of these variants were selected for further analyses of their associations with major diseases (cancer and CHD) and physiological aging changes. Gene-smoking interactions contributed to these effects. Genes closest to detected variants appear to be involved in similar biological processes and health disorders, as those found in other studies of aging and longevity e.g., in cancer and neurodegeneration. CONCLUSIONS: The impact of genes on longevity may involve trade-off-like effects on different health traits. Genes that influence lifespan represent various molecular functions but may be involved in similar biological processes and health disorders, which could contribute to genetic heterogeneity of longevity and the lack of replication in genetic association studies.