The effects of multiple chronic conditions on hospitalization costs and utilization for ambulatory care sensitive conditions in the United States: a nationally representative cross-sectional study.

BACKGROUND: The presence of multiple chronic conditions (MCCs) complicates inpatient hospital care, leading to higher costs and utilization. Multimorbidity also complicates primary care, increasing the likelihood of hospitalization for ambulatory care sensitive conditions. The purpose of this study was to evaluate how MCCs relate to inpatient hospitalization costs and utilization for ambulatory care sensitive conditions. METHODS: The 2012 Agency for Healthcare Research and Quality (AHRQ) Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases (SID) provided data to carry out a cross-sectional analysis of 1.43 million claims related to potentially preventable hospitalizations classified by the AHRQ Prevention Quality Indicator (PQI) composites. Categories of MCCs (0-1, 2-3, 4-5, and 6+) were examined in sets of acute, chronic, and overall PQIs. Multivariate models determined associations between categories of MCCs and 1) inpatient costs per stay, 2) inpatient costs per day, and 3) length of inpatient hospitalization. Negative binomial was used to model costs per stay and costs per day. RESULTS: The most common category observed was 2 or 3 chronic conditions (37.8 % of patients), followed by 4 or 5 chronic conditions (30.1 % of patients) and by 6+ chronic conditions (10.1 %). Compared with costs for patients with 0 or 1 chronic condition, hospitalization costs per stay for overall ambulatory care sensitive conditions were 19 % higher for those with 2 or 3 (95 % confidence interval [CI] 1.19-1.20), 32 % higher for those with 4 or 5 (95 % CI 1.31-1.32), and 31 % higher (95 % CI 1.30-3.32) for those with 6+ conditions. Acute condition stays were 11 % longer when 2 or 3 chronic conditions were present (95 % CI 1.11-1.12), 21 % longer when 4 or 5 were present (95 % CI 1.20-1.22), and 27 % longer when 6+ were present (95 % CI 1.26-1.28) compared with those with 0 or 1 chronic condition. Similar results were seen within chronic conditions. Associations between MCCs and total costs were driven by longer stays among those with more chronic conditions rather than by higher costs per day. CONCLUSIONS: The presence of MCCs increased inpatient costs for ambulatory care sensitive conditions via longer hospital stays.

Differences in severity at admission for heart failure between rural and urban patients: the value of adding laboratory results to administrative data.

BACKGROUND: Rural/urban variations in admissions for heart failure may be influenced by severity at hospital presentation and local practice patterns. Laboratory data reflect clinical severity and guide hospital admission decisions and treatment for heart failure, a costly chronic illness and a leading cause of hospitalization among the elderly. Our main objective was to examine the role of laboratory test results in measuring disease severity at the time of admission for inpatients who reside in rural and urban areas. METHODS: We retrospectively analyzed discharge data on 13,998 hospital discharges for heart failure from three states, Hawai'i, Minnesota, and Virginia. Hospital discharge records from 2008 to 2012 were derived from the State Inpatient Databases of the Healthcare Cost and Utilization Project, and were merged with results of laboratory tests performed on the admission day or up to two days before admission. Regression models evaluated the relationship between clinical severity at admission and patient urban/rural residence. Models were estimated with and without use of laboratory data. RESULTS: Patients residing in rural areas were more likely to have missing laboratory data on admission and less likely to have abnormal or severely abnormal tests. Rural patients were also less likely to be admitted with high levels of severity as measured by the All Patient Refined Diagnosis Related Groups (APR-DRG) severity subclass, derivable from discharge data. Adding laboratory data to discharge data improved model fit. Also, in models without laboratory data, the association between urban compared to rural residence and APR-DRG severity subclass was significant for major and extreme levels of severity (OR 1.22, 95% CI 1.03-1.43 and 1.55, 95% CI 1.26-1.92, respectively). After adding laboratory data, this association became non-significant for major severity and was attenuated for extreme severity (OR 1.12, 95% CI 0.94-1.32 and 1.43, 95% CI 1.15-1.78, respectively). CONCLUSION: Heart failure patients from rural areas are hospitalized at lower severity levels than their urban counterparts. Laboratory test data provide insight on clinical severity and practice patterns beyond what is available in administrative discharge data.

The relationship among caregiving characteristics, caregiver strain, and health-related quality of life: evidence from the Survey of the Health of Wisconsin.

PURPOSE: In order to better understand how family caregiving may contribute to poor health outcomes, this study sought to determine (1) if and to what extent caregiving characteristics were associated with caregiver strain and health-related quality of life (HRQoL), and (2) whether caregiver strain mediated this association. METHODS: Data were from the 2008-2010 Survey of the Health of Wisconsin, a representative sample of Wisconsin adults aged 21-74 years. Participants completed questionnaires about their caregiving, sociodemographics, and HRQoL; 264 caregivers were identified. Staged generalized additive models assessed the associations among caregiving characteristics, caregiver strain, and HRQoL; survey weights were applied to account for the complex sampling design. RESULTS: More hours per week of care and greater duration of caregiving were associated with higher levels of strain. Greater caregiver strain was in turn associated with worse mental HRQoL. However, most caregiving characteristics were not directly associated with mental or physical HRQoL. CONCLUSIONS: The findings suggest a chains-of-risk model in which caregiving may increase strain, which may in turn adversely influence mental HRQoL. Using this perspective to refine interventions may improve our ability to support caregivers on practice and policy levels.

Association between informal caregiving and cellular aging in the survey of the health of wisconsin: the role of caregiving characteristics, stress, and strain.

The pathophysiological consequences of caregiving have not been fully elucidated. We evaluated how caregiving, stress, and caregiver strain were associated with shorter relative telomere length (RTL), a marker of cellular aging. Caregivers (n = 240) and some noncaregivers (n = 98) in the 2008-2010 Survey of the Health of Wisconsin, comprising a representative sample of Wisconsin adults aged 21-74 years, reported their sociodemographic, health, and psychological characteristics. RTL was assayed from blood or saliva samples. Median T and S values were used to determine the telomere-to-single copy gene ratio (T/S) for each sample, and log(T/S) was used as the dependent variable in analyses. Multivariable generalized additive models showed that RTL did not differ between caregivers and noncaregivers (difference in log(T/S) = -0.03; P > 0.05), but moderate-to-high levels of stress versus low stress were associated with longer RTL (difference = 0.15; P = 0.04). Among caregivers, more hours per week of care, caring for a young person, and greater strain were associated with shorter RTL (P < 0.05). Caregivers with discordant levels of stress and strain (i.e., low perceived stress/high strain) compared with low stress/low strain had the shortest RTL (difference = -0.24; P = 0.02, Pinteraction = 0.13), corresponding to approximately 10-15 additional years of aging. Caregivers with these characteristics may be at increased risk for accelerated aging. Future work is necessary to better elucidate these relationships and develop interventions to improve the long-term health and well-being of caregivers.

Role of global stress in the health-related quality of life of caregivers: evidence from the Survey of the Health of Wisconsin.

PURPOSE: Informal caregivers play a critical role in the care of individuals who are aging or have disabilities and are at increased risk for poor health outcomes. This study sought to determine whether and to what extent: (1) global stress and health-related quality of life (HRQoL) differed between caregivers and non-caregivers; (2) global stress mediated the relationship between caregiving status and HRQoL; and (3) caregiver strain (i.e., stress attributable to caregiving) was associated with worse HRQoL after accounting for global stress. METHODS: Cross-sectional data were from the 2008-2010 Survey of the Health of Wisconsin, a representative sample of adults aged 21-74 years. Participants (n = 1,364) completed questionnaires about caregiving status, sociodemographics, global stress, and HRQoL. Staged generalized additive models assessed the impact of caregiving on HRQoL and the role of caregiver strain and global stress in this relationship. RESULTS: In the last 12 months, 17.2% of the sample reported caregiving. Caregivers reported worse mental HRQoL than non-caregivers (ß -1.88, p = 0.02); global stress mediated this relationship (p < 0.01). Caregivers with the highest levels of strain reported worse mental and physical HRQoL (ß -7.12, p < 0.01), and caregivers with the lowest levels of strain reported better mental HRQoL (ß 2.06, p = 0.01) than non-caregivers; these associations were attenuated by global stress (p < 0.01). CONCLUSION: Global stress, rather than caregiving per se, contributes to poor HRQoL among caregivers, above and beyond the effect of caregiving strain. Screening, monitoring, and reducing stress in multiple life domains presents an opportunity to improve HRQoL outcomes for caregivers.

The associations between a polygenic score, reproductive and menstrual risk factors and breast cancer risk.

We evaluated whether 13 single nucleotide polymorphisms (SNPs) identified in genome-wide association studies interact with one another and with reproductive and menstrual risk factors in association with breast cancer risk. DNA samples and information on parity, breastfeeding, age at menarche, age at first birth, and age at menopause were collected through structured interviews from 1,484 breast cancer cases and 1,307 controls who participated in a population-based case-control study conducted in three US states. A polygenic score was created as the sum of risk allele copies multiplied by the corresponding log odds estimate. Logistic regression was used to test the associations between SNPs, the score, reproductive and menstrual factors, and breast cancer risk. Nonlinearity of the score was assessed by the inclusion of a quadratic term for polygenic score. Interactions between the aforementioned variables were tested by including a cross-product term in models. We confirmed associations between rs13387042 (2q35), rs4973768 (SLC4A7), rs10941679 (5p12), rs2981582 (FGFR2), rs3817198 (LSP1), rs3803662 (TOX3), and rs6504950 (STXBP4) with breast cancer. Women in the score's highest quintile had 2.2-fold increased risk when compared to women in the lowest quintile (95 % confidence interval: 1.67-2.88). The quadratic polygenic score term was not significant in the model (p = 0.85), suggesting that the established breast cancer loci are not associated with increased risk more than the sum of risk alleles. Modifications of menstrual and reproductive risk factors associations with breast cancer risk by polygenic score were not observed. Our results suggest that the interactions between breast cancer susceptibility loci and reproductive factors are not strong contributors to breast cancer risk.

Prospective studies of total and ionized serum calcium in relation to incident and fatal ovarian cancer.

OBJECTIVE: Biological markers that could aid in the detection of ovarian cancer are urgently needed. Many ovarian cancers express parathyroid hormone-related protein, which acts to raise calcium levels in serum. Thus, we hypothesized that high serum calcium levels might predict ovarian cancer. METHODS: We examined the associations between total and ionized serum calcium and ovarian cancer mortality in the Third National Health and Nutrition Survey (NHANES III) using Cox proportional hazard models. We then examined the associations of serum calcium with incident ovarian cancer in a second prospective cohort, the NHANES Epidemiological Follow-up Study (NHEFS). RESULTS: There were eleven deaths from ovarian cancer over 95,556 person-years of follow-up in NHANES III. After multivariable adjustment, the risk for fatal ovarian cancer was 52% higher for each 0.1 mmol/L increase in total serum calcium (RH=1.52, 95% CI 1.06-2.19) and 144% higher for each 0.1 mmol/L increase in ionized serum calcium (RH=2.44, 95% CI=1.45-4.09). Associations persisted after adjusting for nulliparity and the use of oral contraceptives. Eight incident ovarian cancers occurred over 31,089 person-years of follow-up in the NHEFS. After adjusting for covariates, there was a 63% higher risk for ovarian cancer with each 0.1 mmol/L increase in total serum calcium (95% CI 1.14-2.34). Similar results were observed for albumin-adjusted serum calcium. CONCLUSIONS: Higher serum calcium may be a biomarker of ovarian cancer. This is the first report of prospective positive associations between indices of calcium in serum and ovarian cancer. Our findings require confirmation in other cohorts.

The vitamin D pathway and mammographic breast density among postmenopausal women.

Laboratory studies have demonstrated that vitamin D has a number of chemopreventive properties, and that these properties may be mediated or modified by other molecules in the vitamin D pathway, such as parathyroid hormone (PTH) or calcium. However, there is little epidemiologic data exploring the effects of vitamin D on breast cancer risk in the context of these other molecules. We examined a panel of molecules in the vitamin D pathway in relation to mammographic breast density, a marker of breast cancer risk, in the Wisconsin Breast Density Study. A total of 238 postmenopausal women (ages 55-70, with no history of postmenopausal hormone use) were enrolled from mammography clinics in Madison, Wisconsin. Subjects provided blood samples that were analyzed for levels of 25-hydroxy vitamin D [25(OH)D], PTH, insulin-like growth factor-1 (IGF-1), IGF-binding protein 3 (IGFBP-3), retinol, and calcium. Percent breast density was measured using Cumulus software. In age-adjusted analyses there was a positive association between 25(OH)D and percent breast density (P = 0.05; mean percent density = 11.3% vs. 15.6% for 1st vs. 4th quartile of 25(OH)D). Breast density was inversely associated with PTH (P = 0.05; 16.0% vs. 11.4% for Q1 vs. Q4) and positively associated with the IGF-1:IGFBP-3 molar ratio (P = 0.02; 11.9% vs. 15.6% for Q1 vs. Q4). However, these associations were all null after further adjustment for body mass index (BMI; P > 0.25). The independent relation between 25(OH)D and breast density remained null among subgroups defined by BMI and serum levels of retinol, calcium, and estradiol. These results suggest no strong independent associations between the circulating molecules of the vitamin D pathway and mammographic breast density in postmenopausal women. While it remains possible that vitamin D could influence breast cancer risk, our results suggest that such an effect would be mediated through pathways other than breast density.

Incorporating harms into the weighting of the revised Agency for Healthcare Research and Quality Patient Safety for Selected Indicators Composite (Patient Safety Indicator 90).

OBJECTIVE: To reweight the Agency for Healthcare Research and Quality Patient Safety for Selected Indicators Composite (Patient Safety Indicator [PSI] 90) from weights based solely on the frequency of component PSIs to those that incorporate excess harm reflecting patients' preferences for outcome-related health states. DATA SOURCES: National administrative and claims data involving hospitalizations in nonfederal, nonrehabilitation, acute care hospitals. STUDY DESIGN: We estimated the average excess aggregate harm associated with the occurrence of each component PSI using a cohort sample for each indicator based on denominator-eligible records. We used propensity scores to account for potential confounding in the risk models for each PSI and weighted observations to estimate the "average treatment effect in the treated" for those with the PSI event. We fit separate regression models for each harm outcome. Final PSI weights reflected both the disutilities and the frequencies of the harms. DATA COLLECTION/EXTRACTION METHODS: We estimated PSI frequencies from the 2012 Healthcare Cost and Utilization Project State Inpatient Databases with present on admission data and excess harms using 2012-2013 Centers for Medicare & Medicaid Services Medicare Fee-for-Service data. PRINCIPAL FINDINGS: Including harms in the weighting scheme changed individual component weights from the original frequency-based weighting. In the reweighted composite, PSIs 11 ("Postoperative Respiratory Failure"), 13 ("Postoperative Sepsis"), and 12 ("Perioperative Pulmonary Embolism or Deep Vein Thrombosis") contributed the greatest harm, with weights of 29.7%, 21.1%, and 20.4%, respectively. Regarding reliability, the overall average hospital signal-to-noise ratio for the reweighted PSI 90 was 0.7015. Regarding discrimination, among hospitals with greater than median volume, 34% had significantly better PSI 90 performance, and 41% had significantly worse performance than benchmark rates (based on percentiles). CONCLUSIONS: Reformulation of PSI 90 with harm-based weights is feasible and results in satisfactory reliability and discrimination, with a more clinically meaningful distribution of component weights.

Medical oncologists' perspectives of the Veterans Affairs National Precision Oncology Program.

BACKGROUND: To support the rising need for testing and to standardize tumor DNA sequencing practices within the U.S. Department of Veterans Affairs (VA)'s Veterans Health Administration (VHA), the National Precision Oncology Program (NPOP) was launched in 2016. We sought to assess oncologists' practices, concerns, and perceptions regarding Next-Generation Sequencing (NGS) and the NPOP. MATERIALS AND METHODS: Using a purposive total sampling approach, oncologists who had previously ordered NGS for at least one tumor sample through the NPOP were invited to participate in semi-structured interviews. Questions assessed the following: expectations for the NPOP, procedural requirements, applicability of testing results, and the summative utility of the NPOP. Interviews were assessed using an open coding approach. Thematic analysis was conducted to evaluate the completed codebook. Themes were defined deductively by reviewing the direct responses to interview questions as well as inductively by identifying emerging patterns of data. RESULTS: Of the 105 medical oncologists who were invited to participate, 20 (19%) were interviewed from 19 different VA medical centers in 14 states. Five recurrent themes were observed: (1) Educational Efforts Regarding Tumor DNA Sequencing Should be Undertaken, (2) Pathology Departments Share a Critical Role in Facilitating Test Completion, (3) Tumor DNA Sequencing via NGS Serves as the Most Comprehensive Testing Modality within Precision Oncology, (4) The Availability of the NPOP Has Expanded Options for Select Patients, and (5) The Completion of Tumor DNA Sequencing through the NPOP Could Help Improve Research Efforts within VHA Oncology Practices. CONCLUSION: Medical oncologists believe that the availability of tumor DNA sequencing through the NPOP could potentially lead to an improvement in outcomes for veterans with metastatic solid tumors. Efforts should be directed toward improving oncologists' understanding of sequencing, strengthening collaborative relationships between oncologists and pathologists, and assessing the role of comprehensive NGS panels within the battery of precision tests.

A prospective study of total and ionized serum calcium and fatal prostate cancer.

We recently reported a significant positive association in the National Health and Nutrition Examination Survey between high levels of total calcium in serum, measured prospectively, and risk of fatal prostate cancer. To confirm this, we examined associations between total and ionized serum calcium and prostate cancer mortality in an independent cohort, the Third National Health and Nutrition Examination Survey. Twenty-five prostate cancer deaths occurred over 56,625 person-years of follow-up. Compared with men in the lowest tertile of total serum calcium, the multivariate-adjusted relative risk for death from prostate cancer for men in the highest tertile was 2.07 (95% confidence interval, 1.06-4.04). For ionized serum calcium, the physiologically active fraction of total serum calcium, the relative risk for men in the highest tertile was 3.18 (95% confidence interval, 1.09-9.28). These findings support the hypothesis that serum calcium is a prospective biomarker of fatal prostate cancer.

Associations of serum sex hormone binding globulin (SHBG) levels with SHBG gene polymorphisms in the CARDIA Male Hormone Study.

In the sex hormone binding globulin (SHBG) gene, a pentanucleotide-repeat polymorphism [(TAAAA)(n)] and a single nucleotide polymorphism (D327N) have been associated with circulating SHBG concentrations in women. Only one study, limited to Scandinavians, has examined these associations in men. Using data from the Coronary Artery Risk Development in Young Adults (CARDIA) Male Hormone Study, the authors assessed associations of SHBG polymorphisms with serum SHBG levels in 511 Black men and 698 White men who had SHBG measured in multiple serum samples collected over an 8-year period from 1987 to 1996 and were aged 20-34 years at the time of the first SHBG measurement. Multivariable repeated-measures analyses were used to assess associations of (TAAAA)(n) and D327N polymorphisms with SHBG concentrations. Results showed statistically significant differences in mean SHBG concentrations for White men with genotypes of (TAAAA) 6/6 (35.1 nmol/liter), 6/x (30.8 nmol/liter), and x/x (29.6 nmol/liter), where x represents a repeat length greater than 6 (p = 0.001). For Black men, the pattern of association was similar, albeit not statistically significant (p = 0.35). There was no relation between D327N genotype and SHBG levels. These results suggest that the (TAAAA)(n) repeat length in the SHBG gene, but not the D327N variant, might contribute to the interindividual variability in serum SHBG levels.

Serum calcium and incident and fatal prostate cancer in the National Health and Nutrition Examination Survey.

We examined the association between serum calcium levels and the risk for prostate cancer using a prospective cohort, the National Health and Nutrition Examination Survey (NHANES) and the NHANES Epidemiologic Follow-up Study. Eighty-five incident cases of prostate cancer and 25 prostate cancer deaths occurred over 46,188 person-years of follow-up. Serum calcium was determined an average of 9.9 years before the diagnosis of prostate cancer. Comparing men in the top with men in the bottom tertile of serum calcium, the multivariable-adjusted relative hazard for fatal prostate cancer was 2.68 (95% confidence interval, 1.02-6.99; P(trend) = 0.04). For incident prostate cancer, the relative risk for the same comparison was 1.31 (95% confidence interval, 0.77-2.20; P(trend) = 0.34). These results support the hypothesis that high serum calcium or a factor strongly associated with it (e.g., high serum parathyroid hormone) increases the risk for fatal prostate cancer. Our finding of a >2.5-fold increased risk for men in the highest tertile of serum calcium is comparable in magnitude with the risk associated with family history and could add significantly to our ability to identify men at increased risk for fatal prostate cancer.

Vitamin D intake and the risk for pancreatic cancer in two cohort studies.

Vitamin D and its analogues exhibit potent antitumor effects in many tissues, including the pancreas. Normal and malignant pancreatic tissues were recently shown to express high levels of vitamin D 1-alpha-hydroxylase, which converts circulating 25-hydroxyvitamin D to active 1,25-dihydroxyvitamin D. We examined associations between dietary intake of vitamin D, calcium, and retinol and subsequent risk for pancreatic cancer. We conducted prospective studies in cohorts of 46,771 men ages 40 to 75 years as of 1986 (the Health Professionals Follow-up Study), and 75,427 women ages 38 to 65 years as of 1984 (the Nurses' Health Study), documenting incident pancreatic cancer through the year 2000. Diet was ascertained by semiquantitative food-frequency questionnaire. We identified 365 incident cases of pancreatic cancer over 16 years of follow-up. Compared with participants in the lowest category of total vitamin D intake (<150 IU/d), pooled multivariate relative risks for pancreatic cancer were 0.78 [95% confidence interval (95% CI), 0.59-1.01] for 150 to 299 IU/d, 0.57 (95% CI, 0.40-0.83) for 300 to 449 IU/d, 0.56 (95% CI, 0.36-0.87) for 450 to 599 IU/d, and 0.59 (95% CI, 0.40-0.88) for >/=600 IU/d (P(trend) = 0.01). These associations may be stronger in men than women. After adjusting for vitamin D intake, calcium and retinol intakes were not associated with pancreatic cancer risk. In two U.S. cohorts, higher intakes of vitamin D were associated with lower risks for pancreatic cancer. Our results point to a potential role for vitamin D in the pathogenesis and prevention of pancreatic cancer.

Serum Calcium and Serum Albumin Are Biomarkers That Can Discriminate Malignant from Benign Pelvic Masses.

BACKGROUND: Biomarkers that aid in the differential diagnosis of malignant pelvic masses from benign ones prior to surgery are needed in order to triage women with malignant masses to appropriate specialist care. Because high albumin-adjusted serum calcium predicted ovarian cancer among women without evidence of disease, we hypothesized that it might predict cancer among women with pelvic masses that were evident radiographically. METHODS: We studied a cohort of 514 women with pelvic masses who underwent resection at Wake Forest University Baptist Medical Center from July 2009 through June 2013. We divided patients into a "training" set, to identify associations in the data, and a "testing" set, to confirm them. Data were obtained from medical records. A best fit model was selected using the Akaike Information Criterion. RESULTS: Albumin-adjusted serum calcium was significantly higher in women with malignant versus benign masses (P = 0.0004). High normocalcemia, i.e., an albumin-adjusted serum calcium ≥ 10 mg/dL, occurred in 53% of women with malignant tumors versus 12% of benign tumors. High normocalcemia was associated with an approximately 14-fold increased risk of malignancy. The best fit model (Overa) included albumin, calcium, and nonlinear terms. Overa achieved an area under the curve of 0.83 with a sensitivity of 72% and specificity of 83%, a positive predictive value of 71% and a negative predictive value of 85%. CONCLUSIONS: A model using serum calcium and serum albumin to predict malignancy in women with pelvic masses has high sensitivity and is economical. IMPACT: Our model can help triage women with ovarian cancer to appropriate surgical care.

Parity, reproductive factors, and the risk of pancreatic cancer in women.

Incidence rates for pancreatic cancer are consistently lower in women than in men. Previous studies suggest that reproductive factors, particularly parity, may reduce pancreatic cancer risk in women. We examined parity, breast feeding history, age at first birth, menstrual factors, and exogenous hormone use in relation to pancreatic cancer risk in a prospective cohort study of women. Information on parity and other reproductive factors was assessed by questionnaires in 1976 and updated biennially. Multivariate relative risks were adjusted for cigarette smoking, body mass index, diabetes, and height. During 22 years of follow-up (1976-1998), 115,474 women contributed 2.4 million years of person time, and 243 cases of pancreatic cancer were identified. Compared with nulliparous women, the relative risk of pancreatic cancer was 0.86 [95% confidence interval (CI), 0.55-1.36] for women with 1-2 births, 0.75 (95% CI, 0.48-1.17) for 3-4 births, and 0.58 (95% CI, 0.34-0.98) for those with >/=5 births after adjusting for other factors. An analysis for linear trend indicates a 10% reduction in risk for each birth (P(trend) = 0.008). Other reproductive factors and exogenous hormone use were not significantly related to pancreatic cancer risk. In this large prospective cohort of women, parity was associated significantly with a reduced risk of pancreatic cancer. Additional studies should examine the physiological or hormonal changes underlying pregnancy or childbirth that may explain this finding.

Breast cancer susceptibility loci in association with age at menarche, age at natural menopause and the reproductive lifespan.

BACKGROUND: Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with breast cancer risk. Some of these loci have unknown functional significance and may mediate the effects of hormonal exposures on breast cancer risk. We examined relationships between breast cancer susceptibility variants and menstrual/reproductive factors using data from two population-based studies. METHODS: The first analysis was based on a sample of 1328 women age 20-74 who participated as controls in a case-control study of breast cancer conducted in three U.S. states. We evaluated the associations between age at menarche, age at natural menopause and the reproductive lifespan with 13 previously identified breast cancer variants. Associations were also examined with a genetic score created as the sum of at-risk alleles across the 13 variants. For validation, significant results were evaluated in a second dataset comprised 1353 women age 43-86 recruited as part of a cohort study in Wisconsin. RESULTS: Neither the genetic score nor any of the 13 variants considered individually were associated with age at menarche or reproductive lifespan. Two SNPs were associated with age at natural menopause; every increase in the minor allele (A) of rs17468277 (CASP8) was associated with a 1.12 year decrease in menopause age (p=0.02). The minor allele (G) of rs10941679 (5p12) was associated with a 1.01 year increase in age at natural menopause (p=0.01). The results were not replicated in the validation cohort (B=-0.61, p=0.14 and B=-0.01, p=.0.98, respectively). CONCLUSIONS: The evaluated variants and reproductive experiences may work through separate pathways to influence breast cancer risk.

Reproductive windows, genetic loci, and breast cancer risk.

PURPOSE: The reproductive windows between age at menarche and age at first birth (standardized age at first birth) and from menarche to menopause (reproductive lifespan) may interact with genetic variants in association with breast cancer risk. METHODS: We assessed this hypothesis in 6131 breast cancer cases and 7274 controls who participated in the population-based Collaborative Breast Cancer Study. Risk factor information was collected through telephone interviews, and DNA samples were collected on a subsample (N= 1484 cases, 1307 controls) to genotype for 13 genome-wide association study-identified loci. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated, and P values for the interaction between reproductive windows and genotypes were obtained by adding cross-product terms to statistical models. RESULTS: For standardized age at first birth, the OR was 1.52 (CI, 1.36-1.71) comparing the highest quintile with the lowest quintile. Carrier status for rs10941679 (5p12) and rs10483813 (RAD51B) appeared to modify this relationship (P = .04 and P = .02, respectively). For reproductive lifespan, the OR comparing the highest quintile with the lowest quintiles was 1.62 (CI, 1.35-1.95). No interactions were detected between genotype and reproductive lifespan (all P > .05). All results were similar regardless of ductal versus lobular breast cancer subtype. CONCLUSIONS: Our results suggest that the reproductive windows are associated with breast cancer risk and that associations may vary by genetic variants.

The association of telomere length with colorectal cancer differs by the age of cancer onset.

OBJECTIVES: Telomeres are nucleoprotein structures that cap the end of chromosomes and shorten with sequential cell divisions in normal aging. Short telomeres are also implicated in the incidence of many cancers, but the evidence is not conclusive for colorectal cancer (CRC). Therefore, the aim of this study was to assess the association of CRC and telomere length. METHODS: In this case-control study, we measured relative telomere length from peripheral blood leukocytes (PBLs) DNA with quantitative PCR in 598 CRC patients and 2,212 healthy controls. RESULTS: Multivariate analysis indicated that telomere length was associated with risk for CRC, and this association varied in an age-related manner; younger individuals (≤50 years of age) with longer telomeres (80-99 percentiles) had a 2-6 times higher risk of CRC, while older individuals (>50 years of age) with shortened telomeres (1-10 percentiles) had 2-12 times the risk for CRC. The risk for CRC varies with extremes in telomere length in an age-associated manner. CONCLUSIONS: Younger individuals with longer telomeres or older individuals with shorter telomeres are at higher risk for CRC. These findings indicate that the association of PBL telomere length varies according to the age of cancer onset and that CRC is likely associated with at minimum two different mechanisms of telomere dynamics.