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PURPOSE: Evidence on the nature of the relationship between patients receiving chemotherapy as an essential part of guideline-concordant cancer care and the onset of Alzheimer's Disease (AD) and other adverse cognitive outcomes has been mixed. Biological mechanisms were proposed to support both a potentially beneficial and an adverse role. To explore the relationship between chemotherapy and onset of AD and other neurocognitive disorders (ND) in colorectal cancer survivors. METHODS: We conducted a retrospective cohort study of 135,834 individuals older than 65 years diagnosed with colorectal cancer between 1998 and 2007, using SEER-Medicare data. A proportional hazards model was used before and after the use of inverse probability weighting to account for populational differences between the chemotherapy and nonchemotherapy groups. Weights were normalized to the total sample size. RESULTS: After inverse probability weighting, chemotherapy was associated with decreased AD risk (hazard ratio [HR]: 0.791; 95% CI: 0.758 to 0.824) and lower risk for the majority of other ND including AD-related diseases (HR: 0.823; CI: 0.802 to 0.844), dementia (permanent mental disorder) (HR: 0.807; CI: 0.782 to 0.832), and dementia (senile) (HR: 0.772; CI: 0.745 to 0.801). The only adverse effect to remain significant was cerebral degeneration (excluding AD) (HR: 1.067; CI: 1.033 to 1.102). The effects for AD remained after treatment was stratified by chemotherapy agent type and remained significant for up to 6 years past diagnosis. CONCLUSION: Chemotherapy use in colorectal cancer survivors demonstrated an association with reduced risk for AD and other ND.

Purpose The aim of the study was to evaluate the relative contributions of incidence, stage-specific relative survival, and stage ascertainment to changes in bladder cancer (BC) prevalence and incidence-based mortality. Methods Partitioning of prevalence and incidence-based mortality trends into their epidemiologic components. Results BC prevalence estimated from our model increased but at monotonically decreasing rates until 2007, after which it decreased again. The main forces underlying observed trends in BC prevalence were relative BC survival, which improved throughout the period, and BC incidence, which increased at a decreasing rate until 2005 and declined thereafter. Mortality of persons ever diagnosed with BC increased at an increasing rate until 1997, increased at a decreasing rate from 1997 to 2005, and decreased thereafter. The primary forces accounting for mortality trends were changes in mortality in the general population, which improved at an increasing rate during most of 1992–2010, the most important factor, and changes in incidence. Stage ascertainment did not improve during 1992–2010. Conclusions Although mortality rates improved, these gains largely reflected improvements in U.S. population survival rather than from improvements in BC-specific outcomes.

Objectives The regions with highest and lowest Alzheimer's disease (AD) mortality across the United States at state/county levels were identified and their contribution to the differences in total mortality rates between these regions was evaluated. The disease, disease group, sex, race/ethnicity, and place-of-death-related inter-region differences that engender the disparity in mortality were quantitatively described. The hypothesis that inter-regional differences in filling out death certificates are a major contributor to differences in AD mortality was tested. Design Retrospective evaluation of death certificate data. Setting The United States. Participants Deceased US residents, 1999-2018. Methods Region-specific age-adjusted mortality rates and group-specific rate decomposition. Results The county clusters with the highest and lowest AD mortality rates were in Washington (WA) and New York (NY), respectively, with other notable high-mortality clusters on the border of Tennessee, Georgia, and Alabama as well as in North Dakota and South Dakota. These patterns were stable over the 1999-2018 period. AD had the highest contribution to total mortality difference between WA and NY (156%, higher in WA), in contrast circulatory diseases had a contribution of comparable magnitude (154%) but were higher in NY. Differences in cause-of-death certificate coding, either through coding of non-AD dementias, or other conditions accompanying a potential AD death could not account for differences in AD mortality between NY and WA. Conclusions Inter-regional differences in filling out death certificates were not a major contributor to variation in AD mortality between the regions with the highest and lowest rates. The respective mitigation of the effects of neural and circulatory diseases and several other high-impact conditions would not negate the disparity in mortality between NY and WA.

Over 97% of individuals diagnosed with ductal carcinoma in situ (DCIS) will choose to receive guideline concordant care (GCC), which was originally designed to treat invasive cancers and is associated with treatment related morbidity. An alternative to GCC is active surveillance (AS) where therapy is delayed until medically necessary. Differences in mortality risk between the two approaches in women age 65+ are analyzed in this study. SEER and Medicare information on treatment during the first year after diagnosis was used to identify three cohorts based on treatment type and timing: GCC (N = 21,772; immediate consent for treatment), AS1 (N = 431; delayed treatment within 365 days), and AS2 (N = 205; no treatment/ongoing AS). A propensity score-based approach provided pseudorandomization between GCC and AS groups and survival was then compared. Strong influence of comorbidities on the treatment received was observed for all age-groups, with the greatest burden observed in the AS2 group. All-cause and breast-cancer-specific mortality hazard ratios (HR) for AS1 were not statistically different from the GCC group; AS2 was associated with notably higher risk for both all-cause (HR:3.54; CI:3.29, 3.82) and breast-cancer-specific (HR:10.73; CI:8.63,13.35) mortality. Cumulative mortality was substantially higher from other causes than from breast cancer, regardless of treatment group. Women managed with AS for DCIS had higher all-cause and breast-cancer-specific mortality. This effect declined after accounting for baseline comorbidities. Delays of up to 12 months in initiation of GCC did not underperform immediate surgery.

Emerging evidence from experimental and clinical research suggests that stress-related genes may play key roles in AD development. The fact that genome-wide association studies were not able to detect a contribution of such genes to AD indicates the possibility that these genes may influence AD non-linearly, through interactions of their products. In this paper, we selected two stress-related genes (GCN2/EIF2AK4 and APP) based on recent findings from experimental studies which suggest that the interplay between these genes might influence AD in humans. To test this hypothesis, we evaluated the effects of interactions between SNPs in these two genes on AD occurrence, using the Health and Retirement Study data on white indidividuals. We found several interacting SNP-pairs whose associations with AD remained statistically significant after correction for multiple testing. These findings emphasize the importance of nonlinear mechanisms of polygenic AD regulation that cannot be detected in traditional association studies. To estimate collective effects of multiple interacting SNP-pairs on AD, we constructed a new composite index, called Interaction Polygenic Risk Score, and showed that its association with AD is highly statistically significant. These results open a new avenue in the analyses of mechanisms of complex multigenic AD regulation.

PURPOSE: Increasing health care costs, longer life expectancy, improved breast cancer (BC) survival, and higher levels of complex comorbidities have important implications for future Medicare expenditures. METHODS: Data from the SEER program linked to Medicare claims records were used. Women with BC (cases) were categorized into 3 groups on the basis of their year of diagnosis (1998, 2003, or 2008) and were propensity score matched to women without a BC diagnosis (controls). All stage and stage-specific longitudinal changes in survival, morbidity levels using the Elixhauser index, and Medicare expenditures in 2018 dollars were calculated and compared. RESULTS: More than 15% of BC cases were diagnosed in patients over the age of 85 years. The prevalence of most comorbidities increased over time. Costs among cases increased between 1998 and 2008. Spending directly correlated with the stage of disease at diagnosis, with the lowest per-patient costs in the ductal carcinoma in situ (DCIS) subgroup ($14,792 in 1998 and $19,652 in 2008) and the highest in those with distant cancer ($37,667 in 1998 and $43,675 in 2008). Assuming no significant changes in the distribution of BC stage or age at diagnosis, the total annual costs of caring for patients with BC in women 65 years of age or older at diagnosis increased by at least $1.1 billion between 1998 and 2008. CONCLUSION: Improvements in BC survivorship are associated with intensive use of health care resources and substantially higher downstream costs among Medicare beneficiaries. Appropriate planning, in both the fiscal and the oncology care infrastructure, is required to prepare the health system for these emerging health care trends.

Longer lifespan is accompanied by a larger number of chronic diseases among older adults. Because of a growing proportion of older adults in the U.S., this brings the problem of age-related morbidity to the forefront as a major contributor to rising medical expenditures. We evaluated 15-year time trends (from 1998 to 2013) in the prevalence of 48 acute and chronic non-cancer diseases and cancers in older U.S. adults aged 65+ and estimated the annual percentage changes of these prevalence trends using SEER-Medicare and HRS-Medicare data. We found that age-adjusted prevalence of cancers of kidney, pancreas, and melanoma, as well as diabetes, renal disease, limb fracture, depression, anemia, weight deficiency, dementia/Alzheimer's disease, drug/medications abuse and several other diseases/conditions increased over time. Conversely, prevalence of myocardial infarction, heart failure, cardiomyopathy, pneumonia/influenza, peptic ulcer, and gastrointestinal bleeding, among others, decreased over time. There are also diseases whose prevalence did not change substantially over time, e.g., a group of fast progressing cancers and rheumatoid arthritis. Analysis of trends of multiple diseases performed simultaneously within one study design with focus on the same time interval and the same population for all diseases allowed us to provide insight into the epidemiology of these conditions and identify the most alarming and/or unexpected trends and trade-offs. The obtained results can be used for health expenditures planning for growing sector of older adults in the U.S.

Despite evident success in clarifying many important features of Alzheimer's disease (AD) the efficient methods of its prevention and treatment are not yet available. The reasons are likely to be the fact that AD is a multifactorial and heterogeneous health disorder with multiple alternative pathways of disease development and progression. The availability of genetic data on individuals participated in longitudinal studies of aging health and longevity, as well as on participants of cross-sectional case-control studies allow for investigating genetic and non-genetic connections with AD and to link the results of these analyses with research findings obtained in clinical, experimental, and molecular biological studies of this health disorder. The objective of this paper is to perform GWAS of AD in several study populations and investigate possible roles of detected genetic factors in developing AD hallmarks and in other health disorders. The data collected in the Framingham Heart Study (FHS), Cardiovascular Health Study (CHS), Health and Retirement Study (HRS) and Late Onset Alzheimer's Disease Family Study (LOADFS) were used in these analyses. The logistic regression and Cox's regression were used as statistical models in GWAS. The results of analyses confirmed strong associations of genetic variants from well-known genes APOE, TOMM40, PVRL2 (NECTIN2), and APOC1 with AD. Possible roles of these genes in pathological mechanisms resulting in development of hallmarks of AD are described. Many genes whose connection with AD was detected in other studies showed nominally significant associations with this health disorder in our study. The evidence on genetic connections between AD and vulnerability to infection, as well as between AD and other health disorders, such as cancer and type 2 diabetes, were investigated. The progress in uncovering hidden heterogeneity in AD would be substantially facilitated if common mechanisms involved in development of AD, its hallmarks, and AD related chronic conditions were investigated in their mutual connection.

Aims To identify how efforts to control the diabetes epidemic and the resulting changes in diabetes mellitus, type II (T2D) incidence and survival have affected the time-trend of T2D prevalence. Methods A newly developed method of trend decomposition was applied to a 5% sample of Medicare administrative claims filed between 1991 and 2012. Results Age-adjusted prevalence of T2D for adults age 65+ increased at an average annual percentage change of 2.31% between 1992 and 2012. Primary contributors to this trend were (in order of magnitude): improved survival at all ages, increased prevalence of T2D prior to age of Medicare eligibility, decreased incidence of T2D after age of Medicare eligibility. Conclusions Health services supported by the Medicare system, coupled with improvements in medical technology and T2D awareness efforts provide effective care for individuals age 65 and older. However, policy maker attention should be shifted to the prevention of T2D in younger age groups to control the increase in prevalence observed prior to Medicare eligibility.

A conceptual difficulty in genetics of age-related phenotypes that make individuals vulnerable to disease in post-reproductive life is genetic heterogeneity attributed to an undefined role of evolution in establishing their molecular mechanisms. Here, we performed univariate and pleiotropic genome-wide meta-analyses of 20 age-related phenotypes leveraging longitudinal information in a sample of 33,431 individuals and dealing with the natural-selection–free genetic heterogeneity. We identified 142 non-proxy single nucleotide polymorphisms (SNPs) with phenotype-specific (18 SNPs) and pleiotropic (124 SNPs) associations at genome-wide level. Univariate meta-analysis identified two novel (11.1%) and replicated 16 SNPs whereas pleiotropic meta-analysis identified 115 novel (92.7%) and nine replicated SNPs. Pleiotropic associations for most novel (93.9%) and all replicated SNPs were strongly impacted by the natural-selection–free genetic heterogeneity in its unconventional form of antagonistic heterogeneity, implying antagonistic directions of genetic effects for directly correlated phenotypes. Our results show that the common genome-wide approach is well adapted to handle homogeneous univariate associations within Mendelian framework whereas most associations with age-related phenotypes are more complex and well beyond that framework. Dissecting the natural-selection–free genetic heterogeneity is critical for gaining insights into genetics of age-related phenotypes and has substantial and unexplored yet potential for improving efficiency of genome-wide analysis.

Purpose To assess the effect of availability of anti-vascular endothelial growth factor (VEGF) therapy on mortality and hospitalizations for acute myocardial infarction (AMI) and stroke over a 5-year follow-up period in United States Medicare beneficiaries newly diagnosed with exudative age-related macular degeneration (AMD) in 2006 compared with control groups consisting of beneficiaries (1) newly diagnosed with exudative AMD at a time when anti-VEGF therapy was not possible and (2) newly diagnosed with nonexudative AMD. Design Retrospective cohort study. Participants Beneficiaries newly diagnosed with exudative and nonexudative AMD in 2000 and 2006 selected from a random longitudinal sample of Medicare 5% claims and enrollment files. Methods Beneficiaries with a first diagnosis of exudative AMD in 2006 were the treatment group; beneficiaries newly diagnosed with exudative AMD in 2000 or nonexudative AMD in 2000 or 2006 were control groups. To deal with potential selection bias, we designed an intent-to-treat study, which controlled for nonadherence to prescribed regimens. The treatment group consisted of patients with clinically appropriate characteristics to receive anti-VEGF injections given that the therapy is available, bypassing the need to monitor whether treatment was actually received. Control groups consisted of patients with clinically appropriate characteristics but first diagnosed at a time when the therapy was unavailable (2000) and similar patients but for whom the therapy was not clinically indicated (2000, 2006). We used a Cox proportional hazard model. Main Outcome Measures All-cause mortality and hospitalization for AMI and stroke during follow-up. Results No statistically significant changes in probabilities of death and hospitalizations for AMI and stroke within a 5-year follow-up period were identified in exudative AMD beneficiaries newly diagnosed in 2006, the beginning of widespread anti-VEGF use, compared with 2000. As an alternative to our main analysis, which excluded beneficiaries from nonexudative AMD group who received anti-VEGF therapies during follow-up, we performed a sensitivity analysis with this group of individuals reincluded (11% of beneficiaries newly diagnosed with nonexudative AMD in 2006). Results were similar. Conclusions Introduction of anti-VEGF agents in 2006 for treating exudative AMD has not posed a threat of increased risk of AMI, stroke, or all-cause mortality.

Background Bladder cancer (BC) is highly prevalent and costly. This study documented cost and use of services for BC care and for other (non-BC) care received over a 15-year follow-up period by a cohort of Medicare beneficiaries diagnosed with BC in 1998. Methods Data came from the Surveillance, Epidemiology and End Results Program linked to Medicare claims. Medicare claims provided data on diagnoses, services provided, and Medicare Parts A and B payments. Cost was actual Medicare payments to providers inflated to 2018 US$. Cost and utilization were BC-related if the claim contained a BC diagnosis code. Otherwise, costs were for “other care.” For utilization, we grouped Part B-covered services into 6 mutually-exclusive categories. Utilization rates were ratios of the count of claims in a particular category during a follow-up year divided by the number of beneficiaries with BC surviving to year-end. Results Cumulatively over 15-years, for all stages combined, total BC-related cost per BC beneficiary was $42,011 (95% Confidence Interval (CI): $42,405–$43,417); other care cost was about twice this number. Cumulative total BC-related cost of 15-year BC survivors for all stages was $43,770 (CI: $39,068–$48,522), intensity of BC-related care was highest during the first year following BC diagnosis, falling substantially thereafter. After follow-up year 5, there were few statistically significant changes in BC-related utilization. Utilization of other care remained constant during follow-up or increased. Conclusions Substantial costs were incurred for non-BC care. While increasing BC survivorship is an important objective, non-BC care would remain a burden to Medicare.

Background Bladder cancer care is costly, including cost to Medicare, but the medical cost associated with bladder cancer patients relative to identical persons without bladder cancer is unknown. Objective To determine incremental bladder cancer cost to Medicare and the impact of diagnosis stage and bladder cancer survival on cost. Design, setting, and participants A case–control study was conducted using 1998–2013 Surveillance, Epidemiology and End Results–Medicare data. Controls were propensity score matched for diagnosis year, age, gender, race, and 31 Elixhauser Comorbidity Index values. Three incident cohorts, 1998 (n = 3136), 2003 (n = 7000), and 2008 (n = 7002), were compared. Outcome measurements and statistical analysis Survival following diagnosis and Medicare payments (in 2018 dollars) were tabulated, and compared between cases and controls. Results and limitations From 1998 to 2008, bladder cancer patients became older and had more comorbidities at diagnosis, although no stage migration or change in survival occurred. Incremental costs (above those associated with controls) were highest during the 1st year after diagnosis and were higher for distant ($47 533) than for regional ($42 403) or localized ($14 304) cancer. Bladder cancer survival was highly stage dependent. After an initial spike in costs lasting 1–2 yrs, monthly costs dropped in survivors but remained higher than for controls. Long-term survivors in the full sample accrued cumulative Medicare costs of $172 426 over 16 yrs—46% higher than for controls. Limitations include omission of indirect costs and reliance on traditional Medicare. Conclusions While a bladder cancer diagnosis incurs initial high Medicare cost, particularly in patients with advanced cancers, the cumulative costs of bladder cancer in long-term survivors are higher still. Bladder cancer prevention saves Medicare money. However, while early detection, better therapies, and life extension of bladder cancer patients are worthwhile goals, they come at the cost of higher Medicare outlays. Patient summary The lifetime cost of bladder cancer, reflecting surveillance, treatment, and management of complications, is substantial. Since care is ongoing, cost increases with the length of life after diagnosis as well as the severity of initial diagnosis.

BACKGROUND Trends in the prevalence of cognitive impairment (CI) based on cognitive assessment instruments are often inconsistent with those of neurocognitive disorders (ND) based on Medicare claims records. OBJECTIVE We hypothesized that improved ascertainment and resulting decrease in disease severity at the time of diagnosis are responsible for this phenomenon. METHODS Using Medicare data linked to the Health and Retirement Study (1992-2012), we performed a joint analysis of trends in CI and ND to test our hypothesis. RESULTS We identified two major contributors to the divergent directions in CI and ND trends: reductions in disease severity explained more than 60% of the differences between CI and ND prevalence over the study period; the remaining 40% was explained by a decrease in the fraction of undiagnosed individuals. DISCUSSION Improvements in the diagnoses of ND diseases were a major contributor to reported trends in ND and CI. Recent forecasts of CI and ND trends in the U.S. may be overly pessimistic.

A new model for disease prevalence based on the analytical solutions of McKendrick-von Foerster’s partial differential equations is developed. Derivation of the model and methods to cross check obtained results are explicitly demonstrated. Obtained equations describe the time evolution of the healthy and unhealthy age-structured sub-populations and age patterns of disease prevalence. The projection of disease prevalence into the future requires estimates of time trends of age-specific disease incidence, relative survival functions, and prevalence at the initial age and year available in the data. The computational scheme for parameter estimations using Medicare data, analytical properties of the model, application for diabetes prevalence, and relationship with partitioning models are described and discussed. The model allows natural generalization for the case of several diseases as well as for modeling time trends in cause-specific mortality rates.

Objective: The objective of this study is to investigate relationships between adherence to recommended screening and medication use and severe macrovascular complications and all-cause mortality among persons aged above 68 years with diabetes mellitus (DM). Method: Data came from a 5% Medicare claims sample of beneficiaries initially diagnosed with DM during 2006-2008; follow-up was up to 7 years. Results: Adherence to screening guidelines led to reduced mortality—hazard ratio (HR) = 0.57, 95% confidence interval [CI] = [0.56, 0.58]; congestive heart failure [CHF], HR = 0.89, CI = [0.87, 0.91]; acute myocardial infarction [AMI], HR = 0.90, CI = [0.85, 0.95]; and stroke/transient ischemic attack [Stroke/TIA], HR = 0.92, CI = [0.87, 0.97]—during follow-up. Recommended medication use led to lower mortality: HR = 0.72, CI = [0.70, 0.73]; CHF, HR = 0.67, CI = [0.66, 0.69]; AMI, HR = 0.68, CI = [0.65, 0.71]; and Stroke/TIA, HR = 0.79, CI = [0.76, 0.83]. Discussion: Elderly persons newly diagnosed with diabetes who adhered to recommended care experienced reduced risk of mortality and severe macrovascular complications.

BACKGROUND This study identifies the effect of intensive drug therapy (IDT) in individuals age 65+ with diabetes (type 2 diabetes mellitus (T2D)) and hypertension on all-cause death, congestive heart failure (CHF), hospitalization for myocardial infarction (MI), and stroke or transient ischemic attack (TIA). METHODS Individuals from the Medicare 5% dataset with hypertension and T2D undergoing IDT for these conditions were propensity score matched to a nonintensive drug-therapy group. Hazard ratios (HRs) were obtained using the Cox proportional hazard model. RESULTS IDT was associated with increased risk of CHF (HR 2.32; 95% confidence interval (CI) 2.32–2.38), MI (HR 4.27; 95% CI 4.05–4.52), and stroke or TIA (HR 1.80; 95% CI 1.70–1.89) but decreased risk of death (HR 0.95; 95% CI 0.93–0.97). Risk for CHF (HR 0.73; 95% CI 0.71–0.73), MI (HR 0.64; 95% CI 0.62–0.67), stroke or TIA (HR 0.82; 95% CI 0.78–0.86), and death (HR 0.29; 95% CI 0.28–0.29) was decreased by adherence to diabetes management guidelines. CONCLUSIONS Use of IDT in a high-risk population delays death but not severe macrovascular outcomes. Protective effects of IDT in high-risk patients likely outweigh polypharmacy-related health concerns.

This paper shows that the effects of causal SNPs on lifespan, estimated through GWAS, may be confounded and the genetic structure of the study population may be responsible for this effect. Simulation experiments show that levels of linkage disequilibrium (LD) and other parameters of the population structure describing connections between two causal SNPs may substantially influence separate estimates of the effect of the causal SNPs on lifespan. This study suggests that differences in LD levels between two causal SNP loci within two study populations may contribute to the failure to replicate previous GWAS findings. The results of this paper also show that successful replication of the results of genetic association studies does not necessarily guarantee proper interpretation of the effect of a causal SNP on lifespan.

Age-related diseases may result from shared biological mechanisms in intrinsic processes of aging. Genetic effects on age-related diseases are often modulated by environmental factors due to their little contribution to fitness or are mediated through certain endophenotypes. Identification of genetic variants with pleiotropic effects on both common complex diseases and endophenotypes may reveal potential conflicting evolutionary pressures and deliver new insights into shared genetic contribution to healthspan and lifespan. Here, we performed pleiotropic meta-analyses of genetic variants using five NIH-funded datasets by integrating univariate summary statistics for age-related diseases and endophenotypes. We investigated three groups of traits: (1) endophenotypes such as blood glucose, blood pressure, lipids, hematocrit, and body mass index, (2) time-to-event outcomes such as the age-at-onset of diabetes mellitus (DM), cancer, cardiovascular diseases (CVDs) and neurodegenerative diseases (NDs), and (3) both combined. In addition to replicating previous findings, we identify seven novel genome-wide significant loci (< 5e-08), out of which five are low-frequency variants. Specifically, from Group 2, we find rs7632505 on 3q21.1 in SEMA5B, rs460976 on 21q22.3 (1 kb from TMPRSS2) and rs12420422 on 11q24.1 predominantly associated with a variety of CVDs, rs4905014 in ITPK1 associated with stroke and heart failure, rs7081476 on 10p12.1 in ANKRD26 associated with multiple diseases including DM, CVDs, and NDs. From Group 3, we find rs8082812 on 18p11.22 and rs1869717 on 4q31.3 associated with both endophenotypes and CVDs. Our follow-up analyses show that rs7632505, rs4905014, and rs8082812 have age-dependent effects on coronary heart disease or stroke. Functional annotation suggests that most of these SNPs are within regulatory regions or DNase clusters and in linkage disequilibrium with expression quantitative trait loci, implying their potential regulatory influence on the expression of nearby genes. Our mediation analyses suggest that the effects of some SNPs are mediated by specific endophenotypes. In conclusion, these findings indicate that loci with pleiotropic effects on age-related disorders tend to be enriched in genes involved in underlying mechanisms potentially related to nervous, cardiovascular and immune system functions, stress resistance, inflammation, ion channels and hematopoiesis, supporting the hypothesis of shared pathological role of infection, and inflammation in chronic age-related diseases.

In this study, we present a new theory of partitioning of disease prevalence and incidence-based mortality and demonstrate how this theory practically works for analyses of Medicare data. In the theory, the prevalence of a disease and incidence-based mortality are modeled in terms of disease incidence and survival after diagnosis supplemented by information on disease prevalence at the initial age and year available in a dataset. Partitioning of the trends of prevalence and mortality is calculated with minimal assumptions. The resulting expressions for the components of the trends are given by continuous functions of data. The estimator is consistent and stable. The developed methodology is applied for data on type 2 diabetes using individual records from a nationally representative 5% sample of Medicare beneficiaries age 65+. Numerical estimates show excellent concordance between empirical estimates and theoretical predictions. Evaluated partitioning model showed that both prevalence and mortality increase with time. The primary driving factors of the observed prevalence increase are improved survival and increased prevalence at age 65. The increase in diabetes-related mortality is driven by increased prevalence and unobserved trends in time-periods and age-groups outside of the range of the data used in the study. Finally, the properties of the new estimator, possible statistical and systematical uncertainties, and future practical applications of this methodology in epidemiology, demography, public health and health forecasting are discussed.

In this study we applied an original method of identifying diseases with high impact on mortality in older U.S. adults over the 1998–2013 period to compile a list of acute and chronic age-related diseases. We analyzed time trends in prevalence and mortality hazard ratios for 48 selected diseases in order to identify both epidemiological changes as well as possible trade-offs in the all-cause mortality risk posed by these diseases over time. We found that the beneficial downward trends in the risk of several high-impact diseases (e.g. myocardial infarction, heart failure, cardiomyopathy, and several solid cancers) is accompanied by increases in prevalence of other conditions many of which, while receiving little attention by the Public Health community, pose significant risk to life (e.g. electrolytes and liquid disbalance, anemia, weight deficiency, septicemia, and chronic kidney disease) and have adverse synergies with co-existing conditions. Since death HRs decrease for diseases with increasing prevalence, these trends could be explained, in part, by improved ascertainment. We conclude that although individuals who reach age 65 in 2013 can expect to live longer than their counterparts from earlier birth-cohorts, this increase in longevity is accompanied by higher levels of multimorbidity and an increased role of diseases previously overshadowed by the effects of high-impact cardiovascular conditions. The expected continuation of this trend past 2013 requires increased attention to the role of interactions between co-existing diseases, their treatment (including potential adverse effects of polypharmacy and other treatment-treatment interactions) and the optimization of prevention strategies for older U.S. adults.

Objective: The aim of this study was to examine the possibility that type 2 diabetes and Alzheimer’s disease may share common behavioral protective factors such as adherence to type 2 diabetes treatment guidelines given that these two diseases have both epidemiological and metabolic similarities. Method : The method used in this study is a retrospective cohort study of 3,797 U.S. Medicare fee-for-service beneficiaries aged 66+ newly diagnosed with type 2 diabetes and without a prior record of Alzheimer’s disease based on the Health and Retirement Study. Results : Results of a left-truncated Cox model showed that adherence reduces the risk of Alzheimer’s disease by 20% to 24%. Other significant effects were college education (hazard ratio [HR]: 0.65; p value: .023), stroke (HR: 1.40; p value: .013), and 4+ limitations in physical functioning (HR: 1.33; p value: .008). Discussion : Risk of Alzheimer’s disease can be reduced by behavioral factors. Possible mechanisms may include earlier start of interventions to reduce blood glucose levels and improve insulin sensitivity.

Increasing proportions of elderly individuals in developed countries combined with substantial increases in related medical expenditures make the improvement of the health of the elderly a high priority today. If the process of aging by individuals is a major cause of age related health declines then postponing aging could be an efficient strategy for improving the health of the elderly. Implementing this strategy requires a better understanding of genetic and non-genetic connections among aging, health, and longevity. We review progress and problems in research areas whose development may contribute to analyses of such connections. These include genetic studies of human aging and longevity, the heterogeneity of populations with respect to their susceptibility to disease and death, forces that shape age patterns of human mortality, secular trends in mortality decline, and integrative mortality modeling using longitudinal data. The dynamic involvement of genetic factors in (i) morbidity/mortality risks, (ii) responses to stresses of life, (iii) multi-morbidities of many elderly individuals, (iv) trade-offs for diseases, (v) genetic heterogeneity, and (vi) other relevant aging-related health declines, underscores the need for a comprehensive, integrated approach to analyze the genetic connections for all of the above aspects of aging-related changes. The dynamic relationships among aging, health, and longevity traits would be better understood if one linked several research fields within one conceptual framework that allowed for efficient analyses of available longitudinal data using the wealth of available knowledge about aging, health, and longevity already accumulated in the research field.

To investigate the effect of prior intravitreal anti-vascular endothelial growth factor (VEGF) injections on surgical and postoperative complication rates associated with cataract surgery in a nationally representative longitudinal sample of elderly persons.Retrospective, longitudinal cohort analysis.A total of 203 643 Medicare beneficiaries who underwent cataract surgery from January 1, 2009, to December 31, 2013.By using the 5% sample of Medicare claims data, the study assessed risks of 3 adverse outcomes after receipt of cataract surgery for beneficiaries with a history of intravitreal injections. Risks of these outcomes in beneficiaries with a history of intravitreal injections relative to those without were calculated using the Cox proportional hazard model.The primary outcome was the risk of subsequent removal of retained lens fragments (RLFs) within 28 days after cataract surgery. Secondary outcomes were a new diagnosis of acute (40 days) or delayed-onset (40+ days) endophthalmitis and risk of a new primary open-angle glaucoma (POAG) diagnosis within 365 days after cataract surgery.Prior intravitreal anti-VEGF injections were associated with a significantly increased risk of subsequent RLF removal within 28 days after cataract surgery (hazard ratio [HR], 2.26; 95% confidence interval [CI], 1.19-4.30). Prior injections were also associated with increased risk of both acute (HR, 2.29; 95% CI, 1.001-5.22) and delayed-onset endophthalmitis (HR, 3.65; 95% CI, 1.65-8.05). Prior injections were not a significant indicator of increased risk of a new POAG diagnosis.A history of intravitreal injections may be a risk factor for cataract surgery-related intraoperative complications and endophthalmitis. Given the frequency of intravitreal injections and cataract surgery, increased preoperative assessment, additional intraoperative caution, and postoperative vigilance are recommended in patients with a history of intravitreal injections undergoing cataract extraction.

Gaining insights into genetic predisposition to age-related diseases and lifespan is a challenging task complicated by the elusive role of evolution in these phenotypes. To gain more insights, we combined methods of genome-wide and candidate-gene studies. Genome-wide scan in the Atherosclerosis Risk in Communities (ARIC) Study (N = 9,573) was used to pre-select promising loci. Candidate-gene methods were used to comprehensively analyze associations of novel uncommon variants in Caucasians (minor allele frequency~2.5%) located in band 2q22.3 with risks of coronary heart disease (CHD), heart failure (HF), stroke, diabetes, cancer, neurodegenerative diseases (ND), and mortality in the ARIC study, the Framingham Heart Study (N = 4,434), and the Health and Retirement Study (N = 9,676). We leveraged the analyses of pleiotropy, age-related heterogeneity, and causal inferences. Meta-analysis of the results from these comprehensive analyses shows that the minor allele increases risks of death by about 50% (p = 4.6×10−9), CHD by 35% (p = 8.9×10−6), HF by 55% (p = 9.7×10−5), stroke by 25% (p = 4.0×10−2), and ND by 100% (p = 1.3×10−3). This allele also significantly influences each of two diseases, diabetes and cancer, in antagonistic fashion in different populations. Combined significance of the pleiotropic effects was p = 6.6×10−21. Causal mediation analyses show that endophenotypes explained only small fractions of these effects. This locus harbors an evolutionary conserved gene-desert region with non-coding intergenic sequences likely involved in regulation of protein-coding flanking genes ZEB2 and ACVR2A. This region is intensively studied for mutations causing severe developmental/genetic disorders. Our analyses indicate a promising target region for interventions aimed to reduce risks of many major human diseases and mortality., Author Summary Biomedical research and medical care are traditionally focused on individual health conditions in order to postpone, ameliorate, or prevent the accumulation of morbidities in late life. An attractive idea is to find factors, which could reduce burden of not just one disease but a major subset of them to efficiently extend healthy lifespan. Here we focus on the analyses of genetic predisposition to risks of major human age-related diseases and mortality. The analyses highlight a locus in band 2q22.3 associated with risks of coronary heart disease, heart failure, stroke, diabetes, cancer, neurodegenerative diseases, and death. Our analyses indicate a promising target region for interventions aimed to reduce risks of many major human diseases and mortality.