Lucy Akushevich

Ovarian Cancer Risk Factors in African-American and White Women

Ovarian cancer is the most lethal gynecologic malignancy in both African-American and white women. Although prevalences of many ovarian cancer risk factors differ markedly between African Americans and whites, there has been little research on how the relative contributions of risk factors may vary between racial/ethnic groups. Using data from a North Carolina case-control study (1999-2008), the authors conducted unconditional logistic regression analyses to calculate odds ratios and 95% confidence intervals for ovarian cancer risk factors in African-American (143 cases, 189 controls) and white (943 cases, 868 controls) women and to test for interactions by race/ethnicity. They also calculated attributable fractions within each racial/ethnic group for the modifiable factors of pregnancy, oral contraceptive use, tubal ligation, and body mass index. Many risk factors showed similar relations across racial/ethnic groups, but tubal ligation and family history of breast or ovarian cancer showed stronger associations among African Americans. Younger age at menarche was associated with risk only in white women. Attributable fractions associated with tubal ligation, oral contraceptive use, and obesity were markedly higher for African Americans. The relative importance of ovarian cancer risk factors may differ for African-American women, but conclusions were limited by the small sample. There is a clear need for further research on etiologic factors for ovarian cancer in African-American women.

Health decline, aging and mortality: how are they related?

The deterioration of human health with age is manifested in changes of thousands of physiological and biological variables. The contribution of some of such changes to the mortality risk may be small and cannot be reliably detected by existing statistical methods. A cumulative index of health/well-being disorders, which counts changes in observed variables on the way of losing health, may be an appropriate way to take the effects of such variables into account. In this paper we investigate regularities of the aging-related changes in human health/well-being/survival status described by such an index using the new version of the quadratic hazard model of human aging and mortality. We found that the shape and the location of the mortality risk, considered as a function of the introduced health-related index, changes with age reflecting the decline in stress resistance and the age-dependence of the “optimal” health/well-being status. Comparison of these results with findings from early studies using the Cox’s-like model of risk function indicates that the results are likely to describe regularities of deterioration in human health during the aging process.

Genital powder use and risk of ovarian cancer: a pooled analysis of 8,525 cases and 9,859 controls

Genital powder use has been associated with risk of epithelial ovarian cancer in some, but not all, epidemiologic investigations, possibly reflecting the carcinogenic effects of talc particles found in most of these products. Whether risk increases with number of genital powder applications and for all histologic types of ovarian cancer also remains uncertain. Therefore, we estimated the association between self-reported genital powder use and epithelial ovarian cancer risk in eight population-based case–control studies. Individual data from each study were collected and harmonized. Lifetime number of genital powder applications was estimated from duration and frequency of use. Pooled ORs were calculated using conditional logistic regression matched on study and age and adjusted for potential confounders. Subtype-specific risks were estimated according to tumor behavior and histology. 8,525 cases and 9,859 controls were included in the analyses. Genital powder use was associated with a modest increased risk of epithelial ovarian cancer [OR, 1.24; 95% confidence interval (CI), 1.15–1.33] relative to women who never used powder. Risk was elevated for invasive serous (OR, 1.20; 95% CI, 1.09–1.32), endometrioid (OR, 1.22; 95% CI, 1.04–1.43), and clear cell (OR, 1.24; 95% CI, 1.01–1.52) tumors, and for borderline serous tumors (OR, 1.46; 95% CI, 1.24–1.72). Among genital powder users, we observed no significant trend (P = 0.17) in risk with increasing number of lifetime applications (assessed in quartiles). We noted no increase in risk among women who only reported nongenital powder use. In summary, genital powder use is a modifiable exposure associated with small-to-moderate increases in risk of most histologic subtypes of epithelial ovarian cancer. Cancer Prev Res; 6(8); 811–21. ©2013 AACR.

Trade-off between cancer and aging: what role do other diseases play? Evidence from experimental and human population studies.

The potential gain in life expectancy which could result from the complete elimination of mortality from cancer in the U.S. would not exceed 3 years if one were to consider cancer independently of other causes of death. In this paper, we review evidence of trade-offs between cancer and aging as well as between cancer and other diseases, which, if taken into account, may substantially increase estimates of gain in life expectancy resulting from cancer eradication. We also used the Multiple Causes of Death (MCD) data to evaluate correlations among mortalities from cancer and other major disorders including heart disease, stroke, diabetes, Alzheimers, Parkinsons diseases, and asthma. Our analyses revealed significant negative correlations between cancer and other diseases suggesting stronger population effects of cancer eradication. Possible mechanisms of the observed dependencies and emerging perspectives of using dependent competing risks models for evaluating the effects of reduction of mortality from cancer on life expectancy are discussed.

Recreational Physical Activity and Ovarian Cancer Risk and Survival

PURPOSE Physical activity may influence ovarian cancer risk and outcomes through effects on ovulation, inflammatory markers, and other processes. We examined associations between self-reported physical activity and ovarian cancer risk and survival in a population-based, case-control study in North Carolina. METHODS The analyses involved 638 epithelial ovarian cancer cases and 683 controls recruited between 1999-2008. Logistic regression analyses were used to assess ovarian cancer risk in relation to reported average physical activity at various time periods. Kaplan-Meier analyses and proportional hazards modeling were used to assess associations between physical activity and survival among ovarian cancer cases. RESULTS Modestly reduced risks for ovarian cancer were observed in some categories of physical activity, but there were no consistent patterns of greater reductions in risk with higher activity levels. Physical activity before diagnosis was not significantly related to ovarian cancer survival overall, but survival was better for women who reported greater than 2 hours of activity/week as compared to those reporting less than 1 hour/week among women who were non-obese (multivariable Hazard ratio = 0.69, 95% confidence interval: 0.47-1.00). CONCLUSIONS Our data provide weak evidence in support of beneficial effects of physical activity on ovarian cancer risk and survival, but results should be interpreted cautiously because of the lack of a clear dose response relation with higher levels of exercise and the likely misclassification of self-reported activity.

A multi-center population-based case–control study of ovarian cancer in African-American women: the African American Cancer Epidemiology Study (AACES)

BackgroundOvarian cancer (OVCA) is the leading cause of death from gynecological cancer, with poorer survival for African American (AA) women compared to whites. However, little is known about risk factors for OVCA in AA. To study the epidemiology of OVCA in this population, we started a collaborative effort in 10 sites in the US. Here we describe the study and highlight the challenges of conducting a study of a lethal disease in a minority population.MethodsThe African American Cancer Epidemiology Study (AACES) is an ongoing, population-based case–control study of OVCA in AA in 10 geographic locations, aiming to recruit 850 women with invasive epithelial OVCA and 850 controls age- and geographically-matched to cases. Rapid case ascertainment and random-digit-dialing systems are in place to ascertain cases and controls, respectively. A telephone survey focuses on risk factors as well as factors of particular relevance for AAs. Food-frequency questionnaires, follow-up surveys, biospecimens and medical records are also obtained.ResultsCurrent accrual of 403 AA OVCA cases and 639 controls exceeds that of any existing study to date. We observed a high proportion (15%) of deceased non-responders among the cases that in part is explained by advanced stage at diagnosis. A logistic regression model did not support that socio-economic status was a factor in advanced stage at diagnosis. Most risk factor associations were in the expected direction and magnitude. High BMI was associated with ovarian cancer risk, with multivariable adjusted ORs and 95% CIs of 1.50 (0.99-2.27) for obese and 1.27 (0.85- 1.91) for morbidly obese women compared to normal/underweight women.ConclusionsAACES targets a rare tumor in AAs and addresses issues most relevant to this population. The importance of the study is accentuated by the high proportion of OVCA cases ascertained as deceased. Our analyses indicated that obesity, highly prevalent in this population (>60% of the cases), was associated with increased OVCA risk. While these findings need to be replicated, they suggest the potential for an effective intervention on the risk in AAs. Upon completion of enrollment, AACES will be the largest epidemiologic study of OVCA in AA women.

Trade-Offs Between Cancer and Other Diseases: Do They Exist and Influence Longevity?

Relationships between aging, disease risks, and longevity are not yet well understood. For example, joint increases in cancer risk and total survival observed in many human populations and some experimental aging studies may be linked to a trade-off between cancer and aging as well as to the trade-off(s) between cancer and other diseases, and their relative impact is not clear. While the former trade-off (between cancer and aging) received broad attention in aging research, the latter one lacks respective studies, although its understanding is important for developing optimal strategies of increasing both longevity and healthy life span. In this paper, we explore the possibility of trade-offs between risks of cancer and selected major disorders. First, we review current literature suggesting that the trade-offs between cancer and other diseases may exist and be linked to the differential intensity of apoptosis. Then we select relevant disorders for the analysis (acute coronary heart disease [ACHD], stroke, asthma, and Alzheimer disease [AD]) and calculate the risk of cancer among individuals with each of these disorders, and vice versa, using the Framingham Study (5209 individuals) and the National Long Term Care Survey (NLTCS) (38,214 individuals) data. We found a reduction in cancer risk among old (80+) men with stroke and in risk of ACHD among men (50+) with cancer in the Framingham Study. We also found an increase in ACHD and stroke among individuals with cancer, and a reduction in cancer risk among women with AD in the NLTCS. The manifestation of trade-offs between risks of cancer and other diseases thus depended on sex, age, and study population. We discuss factors modulating the potential trade-offs between major disorders in populations, e.g., disease treatments. Further study is needed to clarify possible impact of such trade-offs on longevity.

Genetic model for longitudinal studies of aging, health, and longevity and its potential application to incomplete data.

Many longitudinal studies of aging collect genetic information only for a sub-sample of participants of the study. These data also do not include recent findings, new ideas and methodological concepts developed by distinct groups of researchers. The formal statistical analyses of genetic data ignore this additional information and therefore cannot utilize the entire research potential of the data. In this paper, we present a stochastic model for studying such longitudinal data in joint analyses of genetic and non-genetic sub-samples. The model incorporates several major concepts of aging known to date and usually studied independently. These include age-specific physiological norms, allostasis and allostatic load, stochasticity, and decline in stress resistance and adaptive capacity with age. The approach allows for studying all these concepts in their mutual connection, even if respective mechanisms are not directly measured in data (which is typical for longitudinal data available to date). The model takes into account dependence of longitudinal indices and hazard rates on genetic markers and permits evaluation of all these characteristics for carriers of different alleles (genotypes) to address questions concerning genetic influence on aging-related characteristics. The method is based on extracting genetic information from the entire sample of longitudinal data consisting of genetic and non-genetic sub-samples. Thus it results in a substantial increase in the accuracy of statistical estimates of genetic parameters compared to methods that use only information from a genetic sub-sample. Such an increase is achieved without collecting additional genetic data. Simulation studies illustrate the increase in the accuracy in different scenarios for datasets structurally similar to the Framingham Heart Study. Possible applications of the model and its further generalizations are discussed.

Vitamin D receptor (VDR) polymorphisms and risk of ovarian cancer in Caucasian and African American women

OBJECTIVE Polymorphisms in the vitamin D receptor (VDR) gene have been shown in some studies to be associated with the risk of epithelial ovarian cancer (EOC) in Caucasian women. There are no published reports among African Americans. METHODS Case-control data from the North Carolina Ovarian Cancer Study were analyzed using logistic regression to determine the association between seven VDR polymorphisms and EOC in both Caucasians (513 cases, 532 controls) and African Americans (74 cases, 79 controls). In a larger sample of African-Americans (125 cases, 155 controls), we assessed associations between six SNPs in proximity of rs7975232. RESULTS African American women who carried at least one minor allele of rs7975232 were at higher risk for invasive EOC controlling for age and admixture with an odds ratio (OR) for association under the log-additive model of 2.08 (95% confidence interval (CI)=1.19, 3.63, p=0.010). No association was observed between any of the VDR variants and EOC among Caucasians. A larger sample of African Americans revealed a nearly two-fold increased risk of invasive EOC associated with rs7305032, a SNP in proximity to rs7975232 (R(2)=0.369) with a log-additive OR of 1.87 (95% CI=1.20, 2.93, p=0.006). CONCLUSIONS This is the first report showing VDR variants associated with ovarian cancer risk in African American women. A larger study of African American women is needed to confirm these findings. These results imply that vitamin D exposure is a possible modifiable risk factor of ovarian cancer among African Americans.

Dynamic Determinants of Longevity and Exceptional Health

It is well known from epidemiology that values of indices describing physiological state in a given age may influence human morbidity and mortality risks. Studies of connection between aging and life span suggest a possibility that dynamic properties of age trajectories of the physiological indices could also be important contributors to morbidity and mortality risks. In this paper we use data on longitudinal changes in body mass index, diastolic blood pressure, pulse pressure, pulse rate, blood glucose, hematocrit, and serum cholesterol in the Framingham Heart Study participants, to investigate this possibility in depth. We found that some of the variables describing individual dynamics of the age-associated changes in physiological indices influence human longevity and exceptional health more substantially than the variables describing physiological state. These newly identified variables are promising targets for prevention aiming to postpone onsets of common elderly diseases and increase longevity.