Heidi A. Hanson

Effects of BRCA1 and BRCA2 mutations on female fertility

Women with BRCA1/2 mutations have a significantly higher lifetime risk of developing breast or ovarian cancer. We suggest that female mutation carriers may have improved fitness owing to enhanced fertility relative to non-carriers. Here we show that women who are carriers of BRCA1/2 mutations living in natural fertility conditions have excess fertility as well as excess post-reproductive mortality in relation to controls. Individuals who tested positive for BRCA1/2 mutations who linked into multi-generational pedigrees within the Utah Population Database were used to identify putative obligate carriers. We find that women born before 1930 who are mutation carriers have significantly more children than controls and have excess post-reproductive mortality risks. They also have shorter birth intervals and end child-bearing later than controls. For contemporary women tested directly for BRCA1/2 mutations, an era when modern contraceptives are available, differences in fertility and mortality persist but are attenuated. Our findings suggest the need to re-examine the wider role played by BRCA1/2 mutations. Elevated fertility of female mutation carriers indicates that they are more fecund despite their elevated post-reproductive mortality risks.

Neighborhood Design for Walking and Biking: Physical Activity and Body Mass Index

BACKGROUND Neighborhood designs often relate to physical activity and to BMI. PURPOSE Does neighborhood walkability/bikeability relate to BMI and obesity risk and does moderate-to-vigorous physical activity (MVPA) account for some of the relationship? METHODS Census 2000 provided walkability/bikeability measures-block group proportions of workers who walk or bike to work, housing age, and population density-and National Health and Nutrition Examination Study (NHANES 2003-2006) provided MVPA accelerometer measures. Regression analyses (2011-2012) adjusted for geographic clustering and multiple control variables. RESULTS Greater density and older housing were associated with lower male BMI in bivariate analyses, but there were no density and housing age effects in multivariate models. For women, greater proportions of neighborhood workers who walk to work (M=0.02) and more MVPA was associated with lower BMI and lower obesity risk. For men, greater proportions of workers who bike to work (M=0.004) and more MVPA was associated with lower BMI and obesity risk. For both effects, MVPA partially mediated the relationships between walkability/bikeability and BMI. If such associations are causal, doubling walk and bike-to-work proportions (to 0.04 and 0.008) would have -0.3 and -0.33 effects on the average BMIs of adult women and men living in the neighborhood. This equates to 1.5 pounds for a 64-inch-tall woman and 2.3 pounds for a 69-inch-tall man. CONCLUSIONS Although walking/biking to work is rare in the U.S., greater proportions of such workers in neighborhoods relate to lower weight and higher MVPA. Bikeability merits greater attention as a modifiable activity-friendliness factor, particularly for men.

Re-visiting the relationship between neighbourhood environment and BMI: an instrumental variables approach to correcting for residential selection bias

BackgroundA burgeoning literature links attributes of neighbourhoods’ built environments to residents’ physical activity, food and transportation choices, weight, and/or obesity risk. In cross-sectional studies, non-random residential selection impedes researchers’ ability to conclude that neighbourhood environments cause these outcomes.MethodsCross-sectional data for the current study are based on 14,689 non-Hispanic white women living in Salt Lake County, Utah, USA. Instrumental variables techniques are used to adjust for the possibility that neighbourhoods may affect weight but heavier or lighter women may also choose to live in certain neighbourhoods. All analyses control for the average BMI of siblings and thus familial predisposition for overweight/obesity, which is often an omitted variable in past studies.ResultsWe find that cross-sectional analyses relating neighbourhood characteristics to BMI understate the strength of the relationship if they do not make statistical adjustments for the decision to live in a walkable neighbourhood. Standard cross-sectional estimation reveals no significant relationship between neighbourhood walkability and BMI. However, the instrumental variables estimates reveal statistically significant effects.ConclusionsWe find evidence that residential selection leads to an understatement of the causal effects of neighbourhood walkability features on BMI. Although caution should be used in generalizing from research done with one demographic group in a single locale, our findings support the contention that public policies designed to alter neighbourhood walkability may moderately affect the BMI of large numbers of individuals.

Moderate to vigorous physical activity and weight outcomes: does every minute count?

Purpose. The purpose of this study was to test if moderate to vigorous physical activity (MVPA) in less than the recommended ≥ 10-minute bouts related to weight outcomes. Design. Secondary data analysis. Setting. Random sample from the U.S. civilian noninstitutionalized population included in the National Health and Nutrition Examination Survey (NHANES). Participants. A total of 4511 adults aged 18 to 64 years from the 2003–2006 NHANES. Method. Clinically measured body mass index (BMI) and overweight/obese status were regressed on accelerometer measures of minutes per day in higher-intensity long bouts (≥ 10 minutes, ≥ 2020 accelerometer counts per minute [cpm]), higher-intensity short bouts (< 10 minutes, ≥ 2020 cpm), lower-intensity long bouts (≥ 10 minutes, 760–2019 cpm), and lower-intensity short bouts (< 10 minutes, 760–2019 cpm). Socioeconomic and demographic characteristics were controlled. Results. Both higher-intensity short bouts and long bouts of PA related to lower BMI and risk of overweight/obesity. Neither lower-intensity short bouts nor long bouts related to BMI or risk of overweight/obesity Conclusion. The current ≥ 10-minute MVPA bouts guideline was based on health benefits other than weight outcomes. Our findings showed that for weight gain prevention, accumulated higher-intensity PA bouts of < 10 minutes are highly beneficial, supporting the public health promotion message that “every minute counts.”

Subfertility increases risk of testicular cancer: evidence from population-based semen samples

OBJECTIVE To further understand the association between semen quality and cancer risk by means of well defined semen parameters. DESIGN Retrospective cohort study. SETTING Not applicable. PATIENT(S) A total of 20,433 men who underwent semen analysis (SA) and a sample of 20,433 fertile control subjects matched by age and birth year. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Risk of all cancers as well as site-specific results for prostate cancer, testicular cancer, and melanoma. RESULT(S) Compared with fertile men, men with SA had an increased risk of testicular cancer (hazard rate [HR] 3.3). When the characterization of infertility was refined using individual semen parameters, we found that oligozoospermic men had an increased risk of cancer compared with fertile control subjects. This association was particularly strong for testicular cancer, with increased risk in men with oligozoospermia based on concentration (HR 11.9) and on sperm count (HR 10.3). Men in the in the lowest quartile of motility (HR 4.1), viability (HR 6.6), morphology (HR 4.2), or total motile count (HR 6.9) had higher risk of testicular cancer compared with fertile men. Men with sperm concentration and count in the 90th percentiles of the distribution (≥178 and ≥579 × 10(6)/mL, respectively), as well as total motile count, had an increased risk of melanoma (HRs 2.1, 2.7, and 2.0, respectively). We found no differences in cancer risk between azoospermic and fertile men. CONCLUSION(S) Men with SA had an increased risk of testicular cancer which varied by semen quality. Unlike earlier work, we did not find an association between azoospermia and increased cancer risk.

The Male-Female Health-Survival Paradox and Sex Differences in Cohort Life Expectancy in Utah, Denmark and Sweden 1850-1910

PURPOSE In Utah, the prevalence of unhealthy male risk behaviors are lower than in most other male populations, whereas women experience higher mortality risk because of higher fertility rates. Therefore, we hypothesize that the Utah sex differential in mortality would be small and less than in Sweden and Denmark. METHODS Life tables from Utah, Denmark, and Sweden were used to calculate cohort life expectancies for men and women born in 1850-1910. RESULTS The sex difference in cohort life expectancy was similar or larger in Utah when compared with Denmark and Sweden. The change over time in the sex differences in cohort life expectancy was approximately 2 years smaller for active Mormons in Utah than for other groups suggesting lifestyle as an important component for the overall change seen in cohort life expectancy. Sex differences in cohort life expectancy at the age of 50 years were similar for individuals actively affiliated with the Church of Jesus Christ of Latter-day Saints and for Denmark and Sweden. CONCLUSIONS The hypothesis that a smaller sex difference in cohort life expectancies in Utah would be detected in relation to Denmark and Sweden was not supported. In Utah, the male-female differences in life expectancy remain substantial pointing toward biological mechanisms or other unmeasured risk factors.

Geographic scale matters in detecting the relationship between neighbourhood food environments and obesity risk: an analysis of driver license records in Salt Lake County, Utah

Objectives Empirical studies of the association between neighbourhood food environments and individual obesity risk have found mixed results. One possible cause of these mixed findings is the variation in neighbourhood geographic scale used. The purpose of this paper was to examine how various neighbourhood geographic scales affected the estimated relationship between food environments and obesity risk. Design Cross-sectional secondary data analysis. Setting Salt Lake County, Utah, USA. Participants 403 305 Salt Lake County adults 25–64 in the Utah driver license database between 1995 and 2008. Analysis Utah driver license data were geo-linked to 2000 US Census data and Dun & Bradstreet business data. Food outlets were classified into the categories of large grocery stores, convenience stores, limited-service restaurants and full-service restaurants, and measured at four neighbourhood geographic scales: Census block group, Census tract, ZIP code and a 1 km buffer around the residents house. These measures were regressed on individual obesity status using multilevel random intercept regressions. Outcome Obesity. Results Food environment was important for obesity but the scale of the relevant neighbourhood differs for different type of outlets: large grocery stores were not significant at all four geographic scales, limited-service restaurants at the medium-to-large scale (Census tract or larger) and convenience stores and full-service restaurants at the smallest scale (Census tract or smaller). Conclusions The choice of neighbourhood geographic scale can affect the estimated significance of the association between neighbourhood food environments and individual obesity risk. However, variations in geographic scale alone do not explain the mixed findings in the literature. If researchers are constrained to use one geographic scale with multiple categories of food outlets, using Census tract or 1 km buffer as the neighbourhood geographic unit is likely to allow researchers to detect most significant relationships.

Increased Risk of Colorectal Cancer Among Family Members of All Ages, Regardless of Age of Index Case at Diagnosis.

BACKGROUND & AIMS It is not clear whether familial risk of colorectal cancer (CRC) varies with age of index CRC patients or their relatives. We quantified the risk of CRC in first-degree relatives (FDRs), second-degree relatives, and first-cousin relatives of individuals with CRC, stratified by ages and sexes of index patients and ages of relatives. METHODS CRCs diagnosed between 1980 and 2010 were identified from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. Age- and sex-matched CRC-free individuals were selected to form the comparison group. CRC risk in relatives was determined by Cox regression analysis. RESULTS Of 18,208 index patients diagnosed with CRC, the highest familial risk was observed in FDRs of index CRC patients who were diagnosed at an age younger than 40 years (hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.7-3.79). However, familial risk was increased in FDRs even when the index case was diagnosed with cancer at an advanced age (>80 years; HR, 1.76; 95% CI, 1.59-1.94). Ages of relatives and ages of index cases of CRC each affected familial cancer risk; the highest risk was found in young relatives (<50 years) of individuals with early-onset CRC (<40 years; HR, 7.0; 95% CI, 2.86-17.09). CONCLUSIONS All relatives of individuals with CRC are at increased risk for this cancer, regardless of the age of diagnosis of the index patient. Although risk is greatest among young relatives of early-onset CRC cases, relatives of patients diagnosed at advanced ages also have an increased risk.

Recent decline in prostate cancer incidence in the United States, by age, stage, and Gleason score

Prostate cancer incidence is sensitive to screening practices, however the impact of recent screening recommendations from the United States Preventative Services Task Force on prostate cancer incidence by age, stage, race, and Gleason score is unknown. This study described the timing and magnitude of changes in prostate cancer incidence trends in the United States by month of diagnosis, and evaluated trends by age, Gleason score, and stage at diagnosis. We analyzed prostate cancer incidence trends using Surveillance, Epidemiology, and End Results (SEER) program data for men diagnosed with invasive prostate cancer from 2007 through 2012. JoinPoint analysis was used to detect changes in the rate of annual percent change (APC) in prostate cancer incidence for all diagnoses and by age, Gleason score, race, and stage. Prostate cancer incidence declined at an estimated −19.6% APC beginning May 2011. This decline was observed in all age groups. Low‐grade tumors (Gleason score ≤6) showed a steeper decline (−29.1% APC) than high‐grade tumors (Gleason score 8–10: −10.8% APC). Only stage I/II and stage III tumors saw declines (−24.2% and −16.7% APC, respectively). A sharp decline in prostate cancer incidence began before release of the United States Preventative Services Task Force October 2011 draft and May 2012 final screening recommendation. The greatest change occurred with incidence of low‐grade tumors, although there is concern that some high‐grade tumors may now go undetected.

Survival of offspring who experience early parental death: Early life conditions and later-life mortality

We examine the influences of a set of early life conditions (ELCs) on all-cause and cause-specific mortality among elderly individuals, with special attention to one of the most dramatic early events in a childs, adolescents, or even young adults life, the death of a parent. The foremost question is, once controlling for prevailing (and potentially confounding) conditions early in life (family history of longevity, paternal characteristics (SES, age at time of birth, sibship size, and religious affiliation)), is a parental death associated with enduring mortality risks after age 65? The years following parental death may initiate new circumstances through which the adverse effects of paternal death operate. Here we consider the offsprings marital status (whether married; whether and when widowed), adult socioeconomic status, fertility, and later life health status. Adult health status is based on the Charlson Co-Morbidity Index, a construct that summarizes nearly all serious illnesses afflicting older individuals that relies on Medicare data. The data are based on linkages between the Utah Population Database and Medicare claims that hold medical diagnoses data. We show that offspring whose parents died when they were children, but especially when they were adolescents/young adults, have modest but significant mortality risks after age 65. What are striking are the weak mediating influences of later-life comorbidities, marital status, fertility and adult socioeconomic status since controls for these do little to alter the overall association. No beneficial effects of the surviving parents remarriage were detected. Overall, we show the persistence of the effects of early life loss on later-life mortality and indicate the difficulties in addressing challenges at young ages.