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Concept: Study design


Men have a shorter life expectancy compared with women but the underlying factor(s) are not clear. Late-onset, sporadic Alzheimer disease (AD) is a common and lethal neurodegenerative disorder and many germline inherited variants have been found to influence the risk of developing AD. Our previous results show that a fundamentally different genetic variant, i.e., lifetime-acquired loss of chromosome Y (LOY) in blood cells, is associated with all-cause mortality and an increased risk of non-hematological tumors and that LOY could be induced by tobacco smoking. We tested here a hypothesis that men with LOY are more susceptible to AD and show that LOY is associated with AD in three independent studies of different types. In a case-control study, males with AD diagnosis had higher degree of LOY mosaicism (adjusted odds ratio = 2.80, p = 0.0184, AD events = 606). Furthermore, in two prospective studies, men with LOY at blood sampling had greater risk for incident AD diagnosis during follow-up time (hazard ratio [HR] = 6.80, 95% confidence interval [95% CI] = 2.16-21.43, AD events = 140, p = 0.0011). Thus, LOY in blood is associated with risks of both AD and cancer, suggesting a role of LOY in blood cells on disease processes in other tissues, possibly via defective immunosurveillance. As a male-specific risk factor, LOY might explain why males on average live shorter lives than females.

Concepts: Tobacco smoking, Study design, Medical statistics, Neurodegenerative disorders, Odds ratio, Risk, Cancer, Epidemiology


BACKGROUND: Epidemiologic studies have reported inconsistent results regarding coffee consumption and the risk of liver cancer. We performed a meta-analysis of published case–control and cohort studies to investigate the association between coffee consumption and liver cancer. METHODS: We searched Medline, EMBASE, ISI Web of Science and the Cochrane library for studies published up to May 2012. We performed a meta-analysis of nine case–control studies and seven cohort studies. RESULTS: The summary odds ratio (OR) for high vs no/almost never drinkers was 0.50 (95% confidence interval (CI): 0.42–0.59), with no significant heterogeneity across studies (Q = 16.71; P = 0.337; I2 = 10.2%). The ORs were 0.50 (95% CI: 0.40–0.63) for case–control studies and 0.48 (95% CI: 0.38–0.62) for cohort studies. The OR was 0.38 (95% CI: 0.25–0.56) in males and 0.60 (95% CI: 0.33–1.10) in females. The OR was 0.45 (95% CI: 0.36–0.56) in Asian studies and 0.57 (95% CI: 0.44–0.75) in European studies. The OR was 0.39 (95% CI: 0.28–0.54) with no adjustment for a history of liver disease and 0.54 (95% CI: 0.46–0.66) after adjustment for a history of liver disease. CONCLUSIONS: The results of this meta-analysis suggested an inverse association between coffee consumption and liver cancer. Because of the small number of studies, further prospective studies are needed.

Concepts: Study design, Odds ratio, Infectious disease, Evidence-based medicine, MEDLINE, Cochrane Library, Cancer, Epidemiology


Oil and gas development emits known hematological carcinogens, such as benzene, and increasingly occurs in residential areas. We explored whether residential proximity to oil and gas development was associated with risk for hematologic cancers using a registry-based case-control study design.

Concepts: Epidemiology, Oncology, Carcinogen, Cancer, Study design, Case-control study, Benzene, Leukemia


Low muscle strength has been found in late adolescence in individuals diagnosed with Parkinson disease (PD) 30 y later. This study investigated whether this lower muscle strength also may translate into increased risks of falling and fracture before the diagnosis of PD.

Concepts: Osteoporosis, Experimental design, Study design, Actuarial science, Epidemiology


This case-control study was nested in a prospective birth cohort to evaluate whether the presence of enteroviruses in stools was associated with the appearance of islet autoimmunity in the Type 1 Diabetes Prediction and Prevention study in Finland.

Concepts: Study design, Diabetes mellitus type 1, Diabetes mellitus, Cohort study


Successful coexistence between large carnivores and humans is conditional upon effective mitigation of the impact of these species on humans, such as through livestock depredation. It is therefore essential for conservation practitioners, carnivore managing authorities, or livestock owners to know the effectiveness of interventions intended to reduce livestock predation by large carnivores. We reviewed the scientific literature (1990-2016), searching for evidence of the effectiveness of interventions. We found experimental and quasi-experimental studies were rare within the field, and only 21 studies applied a case-control study design (3.7% of reviewed publications). We used a relative risk ratio to evaluate the studied interventions: changing livestock type, keeping livestock in enclosures, guarding or livestock guarding dogs, predator removal, using shock collars on carnivores, sterilizing carnivores, and using visual or auditory deterrents to frighten carnivores. Although there was a general lack of scientific evidence of the effectiveness of any of these interventions, some interventions reduced the risk of depredation whereas other interventions did not result in reduced depredation. We urge managers and stakeholders to move towards an evidence-based large carnivore management practice and researchers to conduct studies of intervention effectiveness with a randomized case-control design combined with systematic reviewing to evaluate the evidence.

Concepts: Number needed to harm, Science, Epidemiology, Study design, Case-control study, Relative risk, Cohort study, Predation


OBJECTIVES:Constipation is common in the community, and may affect survival adversely. An association between constipation and development of colorectal cancer (CRC) could be one possible explanation. We performed a systematic review and meta-analysis examining this issue.METHODS:We searched MEDLINE, EMBASE, and EMBASE Classic (through July 2012). Eligible studies were cross-sectional surveys, cohort studies, or case-control studies reporting the association between constipation and CRC. For cross-sectional surveys and cohort studies, we recorded number of subjects with CRC according to the constipation status, and for case-control studies, number of subjects with constipation according to CRC status were recorded. Study quality was assessed according to published criteria. Data were pooled using a random effects model, and the association between CRC and constipation was summarized using an odds ratio (OR) with a 95% confidence interval (CI).RESULTS:The search strategy identified 2,282 citations, of which 28 were eligible. In eight cross-sectional surveys, presence of constipation as the primary indication for colonoscopy was associated with a lower prevalence of CRC (OR=0.56; 95% CI 0.36-0.89). There was a trend toward a reduction in odds of CRC in constipation in three cohort studies (OR=0.80; 95% CI 0.61-1.04). The prevalence of constipation in CRC was significantly higher than in controls without CRC in 17 case-control studies (OR=1.68; 95% CI 1.29-2.18), but with significant heterogeneity, and possible publication bias.CONCLUSIONS:Prospective cross-sectional surveys and cohort studies demonstrate no increase in prevalence of CRC in patients or individuals with constipation. The significant association observed in case-control studies may relate to recall bias.Am J Gastroenterol advance online publication, 12 March 2013; doi:10.1038/ajg.2013.52.

Concepts: Constipation, Scientific method, Panel data, Random effects model, Colorectal cancer, Study design, Experimental design, Epidemiology


Cohort studies can be biased by unmeasured confounding. We propose a hybrid ecologic-epidemiologic design called the trend-in-trend design, which requires a strong time-trend in exposure, but is unbiased unless there are unmeasured factors affecting outcome for which there are time-trends in prevalence that are correlated with time-trends in exposure across strata with different exposure trends. Thus, the conditions under which the trend-in-trend study is biased are a subset of those under which a cohort study is biased. The trend-in-trend design first divides the study population into strata based on the cumulative probability of exposure given covariates, which effectively stratifies on time-trend in exposure, provided there is a trend. Next, a covariates-free maximum likelihood model estimates the odds ratio (OR) using data on exposure prevalence and outcome frequency within cumulative probability of exposure strata, across multiple periods. In simulations, the trend-in-trend design produced ORs with negligible bias in the presence of unmeasured confounding. In empiric applications, trend-in-trend reproduced the known positive association between rofecoxib and myocardial infarction (observed OR: 1.2, 95% confidence interval: 1.1, 1.4), and known null associations between rofecoxib and severe hypoglycemia [OR = 1.1 (0.92, 1.3)] and non-vertebral fracture [OR = 0.84 (0.64, 1.1)]. The trend-in-trend method may be useful in settings where there is a strong time-trend in exposure, such as a newly approved drug or other medical intervention.

Concepts: Normal distribution, Relative risk, Study design, Clinical trial, Epidemiology, Experimental design, Cohort study, Scientific method


Antihistamines are commonly used to treat nausea and vomiting of pregnancy (NVP). We re-analyzed the 24 primary studies cited in a 1997 meta-analysis that concluded antihistamine use for NVP was safe as they had been studied in more than 200,000 participating women and the pooled odds ratio for congenital malformations was 0.76 (95% confidence interval [CI]: 0.60-0.94). Our analysis of this meta-analysis showed that 139,414 women were included in 22 original studies involving antihistamines, 129,108 of which were in studies involving doxylamine. In these studies, 23,485 women were exposed to antihistamines, 14,624 of which were exposed to doxylamine. The summary relative risk (cohort studies) and odds ratio (case-control studies) for congenital malformations from antihistamine exposure were 1.09 (95% CI: 1.01-1.18) and 1.04 (95% CI: 0.91-1.19), and for doxylamine exposure, the summary relative risk and odds ratio were 0.94 (95% CI: 0.80-1.10) and 1.07 (95% CI: 0.93-1.23), respectively. Although not a new systematic review, our re-analysis demonstrates that the safety data for antihistamines, and doxylamine in particular, are based on many fewer than 200,000 participating women and exposures, and that doxylamine use is not associated with a decreased risk of malformations as previously reported.

Concepts: Congenital disorder, Study design, Medical statistics, Nausea, Cohort study, Relative risk, Odds ratio, Epidemiology


OBJECTIVES/HYPOTHESIS: Lymphoma of the parotid gland (LPG) is a rare disease. Clinical diagnosis is difficult, due to a lack of specific symptoms and findings. The aim of this study is to evaluate the diagnostic workup based on the analysis of our cases of LPG and to present the stage-dependent treatment outcome. STUDY DESIGN: Retrospective case-control study. METHODS: From 1992 to 2008, 697 patients at our institution underwent surgery because of a parotid tumor. Among 246 malignancies, an LPG was found histologically in 28 cases (4%). Staging was performed according to the Ann Arbor classification, and treatment was performed by radiotherapy and/or chemo/immunotherapy. The patients were retrospectively analyzed. RESULTS: No specific symptoms were found, with the main finding being a unilateral, painless, slowly progressing parotid mass. The sensitivities of imaging and fine-needle aspiration cytology in detecting LPG were 41% and 12%, respectively. Histology was the key to diagnosis, and frozen sections often revealed the diagnosis during surgery, which obviated the need for more extensive surgery in 89% of cases. The 5-year disease-specific survival estimates were 100% and 75% for early tumor stages (I and II) and advanced stages (III and IV), respectively. CONCLUSIONS: When the precise nature of a parotid mass remains obscure after fine-needle aspiration cytology and imaging, but LPG is clinically suspected, surgical tissue sampling with frozen sections appears to be a valid option and can prevent the need for more extensive surgery. The treatment outcome for LPG is favorable.

Concepts: Epidemiology, Study design, Needle aspiration biopsy, Surgery, Warthin's tumor, Case-control study, Parotid gland, Cancer