Chapter 12 - Case-Control Studies - Part I

Does administration of vaginal estrogens increase the risk of venous thromboembolism: A case-control study.

Large-scale retrospective analysis suggests medications and dietary supplements, such as rosuvastatin, ezetimibe, ubiquinone, risedronate, vitamin D, and magnesium, are associated with a lower rate of severe COVID-19 disease.

Genome-wide association studies are carried out to identify unknown genes for a complex trait. Polymorphisms showing the most statistically significant associations are reported and followed up in subsequent confirmatory studies. In addition to the test of association, the statistical analysis provides point estimates of the relationship between the genotype and phenotype at each polymorphism, typically an odds ratio in case-control association studies. The statistical significance of the test and the estimator of the odds ratio are completely correlated. Selecting the most extreme statistics is equivalent to selecting the most extreme odds ratios. The value of the estimator, given the value of the statistical significance depends on the standard error of the estimator and the power of the study. This report shows that when power is low, estimates of the odds ratio from a genome-wide association study, or any large-scale association study, will be upwardly biased. Genome-wide association studies are often underpowered given the low alpha levels required to declare statistical significance and the small individual genetic effects known to characterize complex traits. Factors such as low allele frequency, inadequate sample size and weak genetic effects contribute to large standard errors in the odds ratio estimates, low power and upwardly biased odds ratios. Studies that have high power to detect an association with the true odds ratio will have little or no bias, regardless of the statistical significance threshold. The results have implications for the interpretation of genome-wide association analysis and the planning of subsequent confirmatory stages.

Hepatitis C virus infection and non‐Hodgkin lymphoma: Interesting association or causal relationship?

This article presents the results of a simulation study of the estimation of a common odds ratio in multiple-contingency tables when the data are correlated within clusters. The correlation is modeled by the beta-binomial distribution. The three objectives of the study were to determine (a) the variances, biases, and relative efficiencies of the beta-binomial maximum likelihood estimator (MLE), the binomial MLE, and the Mantel-Haenszel estimator of the common odds ratio; (b) the variances and biases of two estimators of the intracluster correlation coefficient, ρ; and (c) the effectiveness of adjusting variance estimates of the binomial and Mantel-Haenszel estimators using the two estimators of ρ. The simulation shows that increasing the size of the intracluster correlation coefficient increases the variance and the positive bias of all three estimators of the odds ratio. The Mantel-Haenszel estimator displays less variance and bias than the MLE except for large values of Ψ and ρ. An unexpected b...

This article presents the results of a simulation study of the estimation of a common odds ratio in multiple-contingency tables when the data are correlated within clusters. The correlation is modeled by the beta-binomial distribution. The three objectives of the study were to determine (a) the variances, biases, and relative efficiencies of the beta-binomial maximum likelihood estimator (MLE), the binomial MLE, and the Mantel-Haenszel estimator of the common odds ratio; (b) the variances and biases of two estimators of the intracluster correlation coefficient, ρ; and (c) the effectiveness of adjusting variance estimates of the binomial and Mantel-Haenszel estimators using the two estimators of ρ. The simulation shows that increasing the size of the intracluster correlation coefficient increases the variance and the positive bias of all three estimators of the odds ratio. The Mantel-Haenszel estimator displays less variance and bias than the MLE except for large values of Ψ and ρ. An unexpected b...

Several human studies imply that the trace element selenium and its species may influence the onset of neurological disease, including Alzheimer’s dementia (AD). Nevertheless, the literature is conflicting, with reported associations between exposure and risk in opposite direction, possibly due to biases in exposure assessment.After conducting a cohort study that detected an excess AD risk associated with higher levels of inorganic-hexavalent selenium in subjects with mild cognitive impairment (MCI), we investigated the relation between selenium and AD using a case-control study design. We determined cerebrospinal fluid levels of selenium species in 56 MCI participants already included in the cohort study, considered as referents, and in 33 patients with established AD.AD risk was inversely correlated with inorganic selenium species and with the organic form bound to selenoprotein P. Selenium bound to other organo-selenium species was positively correlated with AD risk, suggesting compensatory selenoprotein upregulation following increased oxidative stress. The finding of an increased AD risk associated with inorganic-hexavalent selenium from the cohort study was not replicated.This case-control study yielded entirely different results than those generated by a cohort study with a partially overlapping participant population, suggesting that case-control design does not allow to reliably assess the role of selenium exposure in AD etiology. This inability appears to be due to exposure misclassification, falsely indicating an etiologic role of selenium deficiency likely due to reverse causation, and involving most selenium species. The case-control design may instead lend insights into the pathologic process underlying disease progression.

Background: Risk factors for aquaporin-4 (AQP4+) antibody neuromyelitis optica spectrum disorder (NMOSD) are not well-established. Objective: To investigate demographic and environmental factors associated with NMOSD using a validated questionnaire and case–control design. Methods: We enrolled patients with AQP4 + NMOSD through six Canadian Multiple Sclerosis Clinics. Participants completed the validated Environmental Risk Factors in Multiple Sclerosis Study (EnvIMS) questionnaire. Their responses were compared to those of 956 unaffected controls from the Canadian arm of EnvIMS. We calculated odds ratios (ORs) for the association between each variable and NMOSD using logistic regression and Firth’s procedure for rare events. Results: In 122 participants (87.7% female) with NMOSD, odds of NMOSD in East Asian and Black participants were ⩾8 times that observed in White participants. Birthplace outside Canada was associated with an increased risk of NMOSD (OR = 5.5, 95% confidence interval (CI) = 3.6–8.3) as were concomitant autoimmune diseases (OR = 2.7, 95% CI = 1.4–5.0). No association was observed with reproductive history or age at menarche. Conclusion: In this case–control study, risk of NMOSD in East Asian and Black versus White individuals was greater than that observed in many previous studies. Despite the preponderance of affected women, we did not observe any association with hormonal factors such as reproductive history or age at menarche.

Fish Consumption and Colorectal Cancer Risk in Humans: A Systematic Review and Meta-analysis

Long-term treatment with clozapine and other antipsychotic drugs and the risk of haematological malignancies in people with schizophrenia: a nationwide case-control and cohort study in Finland

Matching

AIMTo perform a systematic review and meta-analysis on proton pump inhibitors (PPIs) therapy and the risk of Clostridium difficile infection (CDI).METHODSWe conducted a systematic search of MEDLINE/PubMed and seven other databases through January 1990 to March 2017 for published studies that evaluated the association between PPIs and CDI. Adult case-control and cohort studies providing information on the association between PPI therapy and the development of CDI were included. Pooled odds ratios (ORs) estimates with 95% confidence intervals (CIs) were calculated using the random effect. Heterogeneity was assessed by I2 test and Cochran’s Q statistic. Potential publication bias was evaluated via funnel plot, and quality of studies by the Newcastle-Otawa Quality Assessment Scale (NOS).RESULTSFifty-six studies (40 case-control and 16 cohort) involving 356683 patients met the inclusion criteria and were analyzed. Both the overall pooled estimates and subgroup analyses showed increased risk for CDI despite substantial statistical heterogeneity among studies. Meta-analysis of all studies combined showed a significant association between PPI users and the risk of CDI (pooled OR = 1.99, CI: 1.73-2.30, P < 0.001) as compared with non-users. The association remained significant in subgroup analyses: by design-case-control (OR = 2.00, CI: 1.68-2.38, P < 0.0001), and cohort (OR = 1.98, CI: 1.51-2.59, P < 0.0001); adjusted (OR = 1.95, CI: 1.67-2.27, P < 0.0001) and unadjusted (OR = 2.02, CI: 1.41-2.91, P < 0.0001); unicenter (OR = 2.18, CI: 1.72-2.75, P < 0.0001) and multicenter (OR = 1.82, CI: 1.51-2.19, P < 0.0001); age ≥ 65 years (OR = 1.93, CI: 1.40-2.68, P < 0.0001) and < 65 years (OR = 2.06, CI: 1.11-3.81, P < 0.01). No significant differences were found in subgroup analyses (test for heterogeneity): P = 0.93 for case-control vs cohort, P = 0.85 for adjusted vs unadjusted, P = 0.24 for unicenter vs multicenter, P = 0.86 for age ≥ 65 years and < 65 years. There was significant heterogeneity across studies (I2 = 85.4%, P < 0.001) as well as evidence of publication bias (funnel plot asymmetry test, P = 0.002).CONCLUSIONThis meta-analysis provides further evidence that PPI use is associated with an increased risk for development of CDI. Further high-quality, prospective studies are needed to assess whether this association is causal.

Association between fruit and vegetable consumption and oral cancer: a meta-analysis of observational studies1,2

Heart failure (HF) aggregates in families, but the heritability of HF has not been determined. Discerning the genetic and environmental contributions to HF risk is important to further helping to identify individuals at risk. Adoption studies may establish the genetic contribution to HF. This nationwide adoption study aimed to determine the heritability of HF. This case-control study and cohort study design used logistic regression for calculating risks of HF in adoptees. Adoptees who were born in Sweden between 1942 and 1990 were linked to their adoptive parents and biological parents. The Swedish Multi-Generation Register was linked to the Swedish Patient Register for information on hospital inpatient and outpatient admissions and to the Swedish Cause of Death Register for the period 1964 through 2015. Heritability (h2 with a standard error) for HF was determined both with Falconer regression and with tetrachoric correlation. Data analysis was completed from July 2017 to April 2018. Heart failure in biological parents and/or adoptive parents. Heritability; risk of HF, expressed as odds ratios. A total of 21 643 adoptees were included (of whom 10 626 [49.1%] were female), as well as 35 016 adoptive parents (14 872 [42.5%] female) and 43 286 biological parents (21 643 [50.0%] female). There were 194 cases of HF in adoptees, 3972 cases of HF in adoptive parents, and 3657 cases of HF in biological parents. The cohort study odds ratio (OR) for heart failure was 1.45 in adoptees (95% CI, 1.04-2.03) for biological parents with HF, compared with those without an affected biological parent. If cardiomyopathies were excluded, this OR was 1.58 (95% CI, 1.03-2.42). The corresponding OR associated with an affected adoptive parent were nonsignificant, both with cardiomyopathies included (OR, 0.83 [95% CI, 0.57-1.20]) and with cardiomyopathies excluded (OR, 0.79 [95% CI, 0.49-1.29]). The heritability of HF per Falconer regression (h2) was 26% (SE, 14%). With exclusion of cardiomyopathies the heritability using Falconer regression was 34% (SE, 18%). Heart failure in a biological parent is an HF risk factor that is worth clinical consideration. The increased heritability of HF suggests that genetic factors are important in HF pathogenesis.

SummaryBackgroundCo-occurrence of inflammatory bowel disease (IBD) and type 1 diabetes (T1D) has been linked to poor clinical outcomes, but evidence on their bidirectional associations remain scarce. This study aims to investigate their bidirectional associations.MethodsA nationwide matched cohort and case–control study with IBD patients identified between 1987 and 2017. The cohort study included 20,314 IBD patients (≤28 years; Crohn’s disease [CD, n = 7277], ulcerative colitis [UC, n = 10,112], and IBD-unclassified [IBD-U, n = 2925]) and 99,200 individually matched reference individuals, with a follow-up until December 2021. The case–control study enrolled 87,001 IBD patients (no age restriction) and 431,054 matched controls. We estimated adjusted hazard ratio (aHR) of incident T1D in the cohort study with flexible parametric survival model and adjusted odds ratio (aOR) of having a prior T1D in the case–control study with conditional logistic regression model, with 95% confidence intervals (CI).FindingsDuring a median follow-up of 14 years, 116 IBD patients and 353 reference individuals developed T1D. Patients with IBD had a higher hazard of developing T1D (aHR = 1.58 [95% CI = 1.27–1.95]). The hazard was increased in UC (aHR = 2.02 [1.51–2.70]) but not in CD or IBD-U. In the case–control study, a total of 1018 (1.2%) IBD patients and 3496 (0.8%) controls had been previously diagnosed with T1D. IBD patients had higher odds of having prior T1D (aOR = 1.36 [1.26–1.46]). Such positive association was observed in all IBD subtypes. The sibling comparison analyses showed similar associations between IBD and T1D (aHR = 1.44 [0.97–2.15] and aOR = 1.32 [1.18–1.49]).InterpretationPatients with IBD had a moderately increased hazard of developing T1D and higher odds of having prior T1D. Their bidirectional associations may be partially independent of shared familial factors.Funding10.13039/100018353European Crohn’s and Colitis Organisation, 10.13039/501100009800Stiftelsen Professor Nanna Svartz Fond, 10.13039/501100003748SSMF (project#: PG-23-0315-H-02), 10.13039/501100009782Ruth and Richard Julin Foundation; and 10.13039/501100006636FORTE (project#: 2016-00424).