Using an age-at-onset phenotype with interval censoring to compare methods of segregation and linkage analysis in a candidate region for elevated systolic blood pressure

BACKGROUND: Genetic studies of complex disorders such as hypertension often utilize families selected for this outcome, usually with information obtained at a single time point. Since age-at-onset for diagnosed hypertension can vary substantially between individuals, a phenotype based on long-term follow up in unselected families can yield valuable insights into this disorder for the general population. METHODS: Genetic analyses were conducted using 2884 individuals from the largest 330 families of the Framingham Heart Study. A longitudinal phenotype was constructed using the age at an examination when systolic blood pressure (SBP) first exceeds 139 mm Hg. An interval for age-at-onset was created, since the exact time of onset was unknown. Time-fixed (sex, study cohort) and time-varying (body mass index, daily cigarette and alcohol consumption) explanatory variables were included. RESULTS: Segregation analysis for a major gene effect demonstrated that the major gene effect parameter was sensitive to the choice for age-at-onset. Linkage analyses for age-at-onset were conducted using 1537 individuals in 52 families. Evidence for putative genes identified on chromosome 17 in a previous linkage study using a quantitative SBP phenotype for these data was not confirmed. CONCLUSIONS: Interval censoring for age-at-onset should not be ignored. Further research is needed to explain the inconsistent segregation results between the different age-at-onset models (regressive threshold and proportional hazards) as well as the inconsistent linkage results between the longitudinal phenotypes (age-at-onset and quantitative)

Physical Activity and Survival After Prostate Cancer

AbstractBackgroundDespite the high global prevalence of prostate cancer (PCa), few epidemiologic studies have assessed physical activity in relation to PCa survival.ObjectiveTo evaluate different types, intensities, and timing of physical activity relative to PCa survival.Design, setting, and participantsA prospective study was conducted in Alberta, Canada, in a cohort of 830 stage II–IV incident PCa cases diagnosed between 1997 and 2000 with follow-up to 2014 (up to 17 yr). Prediagnosis lifetime activity was self-reported at diagnosis. Postdiagnosis activity was self-reported up to three times during follow-up.Outcome measurements and statistical analysisCox proportional hazards models related physical activity to all-cause and PCa-specific deaths and to first recurrence/progression of PCa.Results and limitationsA total of 458 deaths, 170 PCa-specific deaths, and, after first follow-up, 239 first recurrences/progressions occurred. Postdiagnosis total activity (>119 vs ≤42 metabolic equivalent [MET]-hours/week per year) was associated with a significantly lower all-cause mortality risk (hazard ratio [HR]: 0.58; 95% confidence interval [CI], 0.42–0.79; p value for trend <0.01). Postdiagnosis recreational activity (>26 vs ≤4 MET-hours/week per year) was associated with a significantly lower PCa-specific mortality risk (HR: 0.56; 95% CI, 0.35–0.90; p value for trend = 0.01). Sustained recreational activity before and after diagnosis (>18–20 vs <7–8 MET-hours/week per year) was associated with a lower risk of all-cause mortality (HR: 0.66; 95% CI, 0.49–0.88). Limitations included generalisability to healthier cases and an observational study design.ConclusionsThese findings support emerging recommendations to increase physical activity after the diagnosis of PCa and would inform a future exercise intervention trial examining PCa outcomes.Patient summaryIn a 17-yr prostate cancer (PCa) survival study, men who survived at least 2 yr who were more physically active postdiagnosis or performed more recreational physical activity before and after diagnosis survived longer. Recreational physical activity after diagnosis was associated with a lower risk of PCa death

Physical Activity and Survival After Prostate Cancer

AbstractBackgroundDespite the high global prevalence of prostate cancer (PCa), few epidemiologic studies have assessed physical activity in relation to PCa survival.ObjectiveTo evaluate different types, intensities, and timing of physical activity relative to PCa survival.Design, setting, and participantsA prospective study was conducted in Alberta, Canada, in a cohort of 830 stage II–IV incident PCa cases diagnosed between 1997 and 2000 with follow-up to 2014 (up to 17 yr). Prediagnosis lifetime activity was self-reported at diagnosis. Postdiagnosis activity was self-reported up to three times during follow-up.Outcome measurements and statistical analysisCox proportional hazards models related physical activity to all-cause and PCa-specific deaths and to first recurrence/progression of PCa.Results and limitationsA total of 458 deaths, 170 PCa-specific deaths, and, after first follow-up, 239 first recurrences/progressions occurred. Postdiagnosis total activity (>119 vs ≤42 metabolic equivalent [MET]-hours/week per year) was associated with a significantly lower all-cause mortality risk (hazard ratio [HR]: 0.58; 95% confidence interval [CI], 0.42–0.79; p value for trend <0.01). Postdiagnosis recreational activity (>26 vs ≤4 MET-hours/week per year) was associated with a significantly lower PCa-specific mortality risk (HR: 0.56; 95% CI, 0.35–0.90; p value for trend = 0.01). Sustained recreational activity before and after diagnosis (>18–20 vs <7–8 MET-hours/week per year) was associated with a lower risk of all-cause mortality (HR: 0.66; 95% CI, 0.49–0.88). Limitations included generalisability to healthier cases and an observational study design.ConclusionsThese findings support emerging recommendations to increase physical activity after the diagnosis of PCa and would inform a future exercise intervention trial examining PCa outcomes.Patient summaryIn a 17-yr prostate cancer (PCa) survival study, men who survived at least 2 yr who were more physically active postdiagnosis or performed more recreational physical activity before and after diagnosis survived longer. Recreational physical activity after diagnosis was associated with a lower risk of PCa death

Analysis of incidence and prognostic factors for ipsilateral breast tumour recurrence and its impact on disease-specific survival of women with node-negative breast cancer: a prospective cohort study

INTRODUCTION: This study had three aims: to establish the incidence of ipsilateral breast tumour recurrence (IBTR) in a community treatment setting, to evaluate known factors – in particular younger age (< 40 years) – predictive for local recurrence, and to assess the impact of local recurrence on disease-specific survival (DSS). METHODS: A consecutive series of 1,540 women with node-negative breast cancer, diagnosed between the ages of 18–75 years, were prospectively accrued between September 1987 and September 1999. All had undergone a resection of the primary breast cancer with clear margins, an axillary lymph node dissection with a minimum of four sampled nodes, and breast-conserving surgery (of any type). RESULTS: During the study follow-up period, 98 (6.4%) IBTRs and 117 (7.6%) deaths from or with breast cancer were observed. The median time to IBTR was 3.1 years and to death from or with disease was 4.3 years. In the multivariate Cox proportional hazards (PH) regression model for IBTR with adjuvant therapy factors, independent risk factors included age < 40 years (relative risk (RR) = 1.89, 95% confidence interval (CI) of 1.00 – 3.58), presence of intraductal disease (RR = 1.81, 95% CI = 1.15–2.85) and histological grade ('G2' or G3 versus G1: RR = 1.59, 95% CI = 0.87–2.94). In the multivariate Cox PH regression model for DSS with adjuvant therapy factors, independent risk factors included previous IBTR (RR = 2.58, 95% CI = 1.41–4.72), tumor size (1–2 cm versus < 1 cm: RR = 1.95, 95% CI = 1.05–3.64, > 2 cm versus < 1 cm: RR = 2.94, 95% CI = 1.56–5.56), progesterone receptor status (negative or equivocal versus positive or unknown: RR = 2.15, 95% CI = 1.36–3.39), lymphatic invasion (RR = 1.78, 95% CI = 1.17–2.72), and histological grade ('G2' or G3 versus G1: RR = 8.59, 95% CI = 2.09–35.36). The effects of competing risks could be ignored. CONCLUSION: The Cox PH analyses confirmed the importance of known risk factors for IBTR and DSS in a community treatment setting. This study also revealed that the early occurrence of an IBTR is associated with a relatively poor five-year survival rate

Penetrance of HNPCC-related cancers in a retrolective cohort of 12 large Newfoundland families carrying a MSH2 founder mutation: an evaluation using modified segregation models

<p>Abstract</p> <p>Background</p> <p>Accurate risk (penetrance) estimates for associated phenotypes in carriers of a major disease gene are important for genetic counselling of at-risk individuals. Population-specific estimates of penetrance are often needed as well. Families ascertained from high-risk disease clinics provide substantial data to estimate penetrance of a disease gene, but these estimates must be adjusted for possible specific sources of bias.</p> <p>Methods</p> <p>A cohort of 12 independently ascertained HNPCC families harbouring a founder MSH2 mutation was identified from a cancer genetics clinic in St. John's, Newfoundland, Canada. Carrier status was known for 247 family members but phenotype information on up to 85 additional relatives with unknown carrier status was available; using modified segregation models these additional individuals could be included in the analyses. Three HNPCC-related phenotypes were evaluated as age at diagnosis of: any HNPCC cancer (first cancer), colorectal cancer (CRC), and endometrial cancer (EC) for females.</p> <p>Results</p> <p>Lifetime (age 70) risk estimates for male and female carriers were similar for developing any HNPCC cancer (Males = 98.2%, 95% Confidence Interval (CI) = (93.8%, 99.9%); Females = 92.8%, 95% CI = (82.4%, 99.1%)) but female carriers experienced substantially reduced lifetime risk for developing CRC compared to male carriers (Females = 38.9%, 95% CI = (24.2%, 62.1%); Males = 84.5%, 95% CI = (67.3%, 91.3%)). Female non-carriers had very low lifetime risk for these two outcomes while male non-carriers had lifetime risks intermediate to the female carriers and non-carriers. Female carriers had a lifetime risk of developing EC of 82.4%. Relative risks for developing any HNPCC cancer (carriers relative to non-carriers) were substantially greater for females compared to their male counterparts (Females = 54.8, 95%CI = (4.4, 379.8); Males = 9.7, 95% CI = (0.3, 23.8)). Relative risks for developing CRC at age 70 were substantially greater for females compared to their male counterparts (Females = 23.7, 95%CI = (5.6, 137.9); Males = 6.8%, 95% CI = (2.3, 66.2)). However, the risk of developing CRC decreased with age among both genders.</p> <p>Conclusion</p> <p>The proposed modified segregation-based models used to estimate age-specific risks for HNPCC phenotypes can reduce bias due to ascertainment and missing genotype information as well as provide estimates of absolute and relative risks.</p

Polynomial spline estimation of partially linear single-index proportional hazards regression models

The Cox proportional hazards (PH) model usually assumes linearity of the covariates on the log hazard function, which may be violated because linearity cannot always be guaranteed. We propose a partially linear single-index proportional hazards regression model, which can model both linear and nonlinear covariate effects on the log hazard in the proportional hazards model. We adopt a polynomial spline smoothing technique to model the structured nonparametric single-index component for the nonlinear covariate effects. This method can reduce the dimensionality of the covariates being modeled, while, at the same time, can provide efficient estimates of the covariate effects. A two-step iterative algorithm to estimate the nonparametric component and the covariate effects is used for facilitating implementation. Asymptotic properties of the estimators are derived. Monte Carlo simulation studies are presented to compare the new method with the standard Cox linear PH model and some other comparable models. A case study with clinical trial data is presented for illustration.

Using an age-at-onset phenotype with interval censoring to compare methods of segregation and linkage analysis in a candidate region for elevated systolic blood pressure-1

<p><b>Copyright information:</b></p><p>Taken from "Using an age-at-onset phenotype with interval censoring to compare methods of segregation and linkage analysis in a candidate region for elevated systolic blood pressure"</p><p>http://www.biomedcentral.com/1471-2156/4/s1/S84</p><p>BMC Genetics 2003;4(Suppl 1):S84-S84.</p><p>Published online 31 Dec 2003</p><p>PMCID:PMC1866524.</p><p></p

Intrapersonal and social environment correlates of leisure-time physical activity for cancer prevention: a cross-sectional study among Canadian adults

Background: Little is known about the intrapersonal and social factors associated with sufficient physical activity (PA) for cancer prevention, which is greater than for cardiovascular health. Methods: 1087 and 1684 randomly selected men and women, age 35–64, completed self-administered questionnaires on PA behavior and psycho-social characteristics. Using gender-stratified logistic regression, we investigated correlates of compliance with Canadian Society for Exercise Physiology PA guidelines for general health (150 min/wk), and the American Cancer Society (ACS; 225 min/wk) and World Cancer Research Fund/Ameri- can Institute for Cancer Research (WCRF/AIRC; 420 min/wk) guidelines for cancer prevention. Results: Only 39% and 19% of men and women met ACS and WCRF/AICR guidelines, respectively. Self-efficacy, scheduling PA and friend social support were positively correlated with recommended PA for cancer prevention. In men, poor self-rated health and perceived negative outcomes were negatively correlated and hypertension was positively correlated with meeting cancer prevention guidelines. For women, not being married and having a companion for PA were positively correlated with meeting cancer prevention guidelines. Conclusions: Few adults participate in sufficient PA for cancer risk reduction. Multidimensional public health strategies that incorporate intrapersonal and social factors and are tailored for each gender are needed to promote PA for cancer prevention

Comparison of Two Automated Targeted Metabolomics Programs to Manual Profiling by an Experienced Spectroscopist for 1H-NMR Spectra

Automated programs that carry out targeted metabolite identification and quantification using proton nuclear magnetic resonance spectra can overcome time and cost barriers that limit metabolomics use. However, their performance needs to be comparable to that of an experienced spectroscopist. A previously analyzed pediatric sepsis data set of serum samples was used to compare results generated by the automated programs rDolphin and BATMAN with the results obtained by manual profiling for 58 identified metabolites. Metabolites were selected using Student&rsquo;s t-tests and evaluated with several performance metrics. The manual profiling results had the highest performance metrics values, especially for sensitivity (76.9%), area under the receiver operating characteristic curve (0.90), precision (62.5%), and testing accuracy based on a neural net (88.6%). All three approaches had high specificity values (77.7&ndash;86.7%). Manual profiling by an expert spectroscopist outperformed two open-source automated programs, indicating that further development is needed to achieve acceptable performance levels

Predictors of CRC Stage at Diagnosis among Male and Female Adults Participating in a Prospective Cohort Study: Findings from Alberta’s Tomorrow Project

Colorectal cancer (CRC) is a leading cause of morbidity and mortality in Canada. CRC screening and other factors associated with early-stage disease can improve CRC treatment efficacy and survival. This study examined factors associated with CRC stage at diagnosis among male and female adults using data from a large prospective cohort study in Alberta, Canada. Baseline data were obtained from healthy adults aged 35–69 years participating in Alberta’s Tomorrow Project. Factors associated with CRC stage at diagnosis were evaluated using Partial Proportional Odds models. Analyses were stratified to examine sex-specific associations. A total of 267 participants (128 males and 139 females) developed CRC over the study period. Among participants, 43.0% of males and 43.2% of females were diagnosed with late-stage CRC. Social support, having children, and caffeine intake were predictors of CRC stage at diagnosis among males, while family history of CRC, pregnancy, hysterectomy, menopausal hormone therapy, lifetime number of Pap tests, and household physical activity were predictive of CRC stage at diagnosis among females. These findings highlight the importance of sex differences in susceptibility to advanced CRC diagnosis and can help inform targets for cancer prevention programs to effectively reduce advanced CRC and thus improve survival