Molecular haplotyping by linking emulsion PCR: analysis of paraoxonase 1 haplotypes and phenotypes

Linking emulsion PCR (LE-PCR) enables formation of minichromosomes preserving phase information of two polymorphic loci, hence the haplotype. Emulsion PCR confines two amplicons of two linked polymorphic sites on a single template molecule to one aqueous-phase droplet. Linking PCR uses biotinylated, overlapping linking primers to connect these amplicons in the droplet. After LE-PCR, unlinked amplicons are removed on streptavidin-coated magnetic beads and single-stranded runoff products are capped by primer extension. Quantitative ASPCR can then be used to ascertain the haplotypes of the two polymorphic loci on the minichromosomes. Using LE-PCR, we determined the human paraoxonase-1 [PON1] molecular haplotypes at three loci (−909g>c, L55M, Q192R) in women who were compound heterozygotes for −909g>c/L55M (n = 89), −909g>c/Q192R (n = 77) and L55M/Q192R (n = 68). We observed a strong association between PON1 substrate specificity (paraoxon/phenylacetate substrate activity ratios) and −909g>c/Q192R haplotype. We have demonstrated here a powerful molecular haplotyping technology that can be applied in population studies

Effect of Palliative Care–Led Meetings for Families of Patients With Chronic Critical Illness: A Randomized Clinical Trial

Family caregivers of patients with chronic critical illness experience significant psychological distress

Mortality among World Trade Center rescue and recovery workers, 2002-2011

BACKGROUND: Rescue and recovery workers responding to the 2001 collapse of the World Trade Center (WTC) sustained exposures to toxic chemicals and have elevated rates of multiple morbidities. METHODS: Using data from the World Trade Center Health Program and the National Death Index for 2002-2011, we examined standardized mortality ratios (SMR) and proportional cancer mortality ratios (PCMR) with indirect standardization for age, sex, race, and calendar year to the U.S. general population, as well as associations between WTC-related environmental exposures and all-cause mortality. RESULTS: We identified 330 deaths among 28,918 responders (SMR 0.43, 95%CI 0.39-0.48). No cause-specific SMRs were meaningfully elevated. PCMRs were elevated for neoplasms of lymphatic and hematopoietic tissue (PCMR 1.76, 95%CI 1.06-2.75). Mortality hazard ratios showed no linear trend with exposure. CONCLUSIONS: Consistent with a healthy worker effect, all-cause mortality among responders was not elevated. There was no clear association between intensity and duration of exposure and mortality. Surveillance is needed to monitor the proportionally higher cancer mortality attributed to lymphatic/hematopoietic neoplasms

Maternal Active and Passive Smoking and Hypertensive Disorders of Pregnancy: Risk with Trimester-Specific Exposures

The inverse association between prenatal smoking and preeclampsia is puzzling, given the increased risks of prematurity and low birthweight associated with both smoking and preeclampsia. We analyzed the Norwegian Mother and Child Birth Cohort (MoBa) to determine whether the associations varied by timing of prenatal smoking

Cancer in World Trade Center responders: Findings from multiple cohorts and options for future study

Background Three longitudinal studies of cancer incidence in varied populations of World Trade Center responders have been conducted. Methods We compared the design and results of the three studies. Results Separate analyses of these cohorts revealed excess cancer incidence in responders for all cancers combined and for cancers of the thyroid and prostate. Methodological dissimilarities included recruitment strategies, source of cohort members, demographic characteristics, overlap between cohorts, assessment of WTC and other occupational exposures and confounders, methods and duration of follow-up, approaches for statistical analysis, and latency analyses. Conclusions The presence of three cohorts strengthens the effort of identifying and quantifying the cancer risk; the heterogeneity in design might increase sensitivity to the identification of cancers potentially associated with exposure. The presence and magnitude of an increased cancer risk remains to be fully elucidated. Continued long-term follow up with minimal longitudinal dropout is crucial to achieve this goal

Immunogenicity of Trivalent Inactivated Influenza Vaccination Received During Pregnancy or Postpartum

To estimate the effects of gestational age and other maternal factors on immunologic responses to influenza vaccination

Cancer Incidence in World Trade Center Rescue and Recovery Workers, 2001–2008

Background: World Trade Center (WTC) rescue and recovery workers were exposed to a complex mix of pollutants and carcinogens. Objective: The purpose of this investigation was to evaluate cancer incidence in responders during the first 7 years after 11 September 2001. Methods: Cancers among 20,984 consented participants in the WTC Health Program were identified through linkage to state tumor registries in New York, New Jersey, Connecticut, and Pennsylvania. Standardized incidence ratios (SIRs) were calculated to compare cancers diagnosed in responders to predicted numbers for the general population. Multivariate regression models were used to estimate associations with degree of exposure. Results: A total of 575 cancers were diagnosed in 552 individuals. Increases above registry-based expectations were noted for all cancer sites combined (SIR = 1.15; 95% CI: 1.06, 1.25), thyroid cancer (SIR = 2.39; 95% CI: 1.70, 3.27), prostate cancer (SIR = 1.21; 95% CI: 1.01, 1.44), combined hematopoietic and lymphoid cancers (SIR = 1.36; 95% CI: 1.07, 1.71), and soft tissue cancers (SIR = 2.26; 95% CI: 1.13, 4.05). When restricted to 302 cancers diagnosed ≥ 6 months after enrollment, the SIR for all cancers decreased to 1.06 (95% CI: 0.94, 1.18), but thyroid and prostate cancer diagnoses remained greater than expected. All cancers combined were increased in very highly exposed responders and among those exposed to significant amounts of dust, compared with responders who reported lower levels of exposure. Conclusion: Estimates should be interpreted with caution given the short follow-up and long latency period for most cancers, the intensive medical surveillance of this cohort, and the small numbers of cancers at specific sites. However, our findings highlight the need for continued follow-up and surveillance of WTC responders

BRCA1 promoter methylation is associated with increased mortality among women with breast cancer

Promoter-CpG island hypermethylation is a common molecular defect in cancer cells. It has been proposed as an alternative mechanism to inactivate BRCA1in the breast where somatic mutations of BRCA1 are rare. To better understand breast cancer etiology and progression, we explored the association between BRCA1 promoter methylation status and prognostic factors as well as survival among women with breast cancer. We also examined whether dietary methyl content and functional polymorphisms of genes involved in one-carbon metabolism influenced the methylation pattern. Promoter methylation of BRCA1 was assessed in 851 archived tumor tissues collected from a population-based study of women diagnosed with invasive or in situ breast cancer in 1996–1997, and who were followed for vital status through the end of 2002. About 59% of the tumors were methylated at the promoter of BRCA1. The BRCA1 promoter methylation was more frequent in invasive cancers (p=0.02) and among premenopausal cases (p=0.05). BRCA1 promoter methylation was associated with increased risk of breast cancer-specific mortality (age-adjusted HR 1.71; 95% CI: 1.05–2.78) and all-cause mortality (age-adjusted HR 1.49; 95% CI: 1.02–2.18). Among dietary methyl intakes in the year prior to the baseline interview examined, cases with lowest quintile of choline intake (<20%) had higher BRCA1 methylation level in the tumor compared to the rest (66.1% vs. 57.7%, p=0.04). Functional polymorphisms in one-carbon metabolism were not correlated with BRCA1 methylation status. Our study is the first epidemiological investigation on the prognostic value of BRCA1 promoter methylation in a large population-based cohort of breast cancer patients. Our results indicate that BRCA1 promoter methylation is an important factor to consider in predicting breast cancer survival

New approximations for the distribution of the r-scan statistic

New approximations are given for the distribution of the length of the ith (i[greater-or-equal, slanted]1) smallest intervals containing r points, when N observations are randomly distributed on the unit interval, with primary emphasis on the case where N is a random variable.Polya-Aeppli distribution Compound Poisson approximation Declumping

The effect of grouping on the power of the Mantel--Haenszel test for the comparison of survival rates

A criterion is found which determines, for a simple case, whether pooling observations increases or decreases the asymptotic efficiency of the Mantel--Haenszel test for treatment effect, in uncensored long term comparative trials in discrete time, under arbitrary one sided alternatives.Pooling asymptotic efficiency C[alpha] test follow-up studies lag model