Baseline Risk Of Disease Research Articles

Efficient risk-based collection of biospecimens in cohort studies: Designing a prospective study of diagnostic performance for multicancer detection tests.

In cohort studies, it can be infeasible to collect specimens on an entire cohort. For example, to estimate sensitivity of multiple Multi-Cancer Detection (MCD) assays, we desire an extra 80mL of cell-free DNA (cfDNA) blood, but this much extra blood is too expensive for us to collect on everyone. We propose a novel epidemiologic study design that efficiently oversamples those at highest baseline disease risk from whom to collect specimens, to increase the number of future cases with cfDNA blood collection. The variance reduction ratio from our risk-based subsample versus a simple random (sub)sample (SRS) depends primarily on the ratio of risk model sensitivity to the fraction of the cohort selected for specimen collection subject to constraining the risk model specificity. In a simulation where we chose 34% of Prostate, Lung, Colorectal, and Ovarian Screening Trial cohort at highest risk of lung cancer for cfDNA blood collection, we could enrich the number of lung cancers 2.42-fold and the standard deviation of lung-cancer MCD sensitivity was 31-33% reduced versus SRS. Risk-based collection of specimens on a subsample of the cohort could be a feasible and efficient approach to collecting extra specimens for molecular epidemiology.

Estimated effects of reductions in processed meat consumption and unprocessed red meat consumption on occurrences of type 2 diabetes, cardiovascular disease, colorectal cancer, and mortality in the USA: a microsimulation study

High consumption of processed meat and unprocessed red meat is associated with increased risk of multiple chronic diseases, although there is substantial uncertainty regarding the relationship for unprocessed red meat. We developed a microsimulation model to estimate how reductions in processed meat and unprocessed red meat consumption could affect rates of type 2 diabetes, cardiovascular disease, colorectal cancer, and mortality in the US adult population. We used data from two versions of the US National Health and Nutrition Examination Survey, one conducted during 2015-16 and one conducted during 2017-18, to create a simulated US population. The starting cohort was restricted to respondents aged 18 years or older who were not pregnant and had 2 days of dietary-recall data. First, we used previously developed risk models to estimate the baseline disease risk of an individual. For type 2 diabetes we used a logistic-regression model and for cardiovascular disease and colorectal cancer we used Cox proportional-hazard models. We then multiplied baseline risk by relative risk associated with individual processed meat and unprocessed red meat consumption. Prevented occurrences of type 2 diabetes, cardiovascular disease, colorectal cancer, and mortality were computed by taking the difference between the incidence in the baseline and intervention scenarios. All stages were repeated for ten iterations to correspond to a 10-year time span. Scenarios were reductions of 5%, 10%, 30%, 50%, 75%, and 100% in grams consumed of processed meat, unprocessed red meat, or both. Each scenario was repeated 50 times for uncertainty analysis. The total number of individual respondents included in the simulated population was 8665, representing 242 021 876 US adults. 4493 (51·9%) of 8665 individuals were female and 4172 (48·1%) were male; mean age was 49·54 years (SD 18·38). At baseline, weighted mean daily consumption of processed meat was 29·1 g, with a 30% reduction being 8·7 g per day, and of unprocessed red meat was 46·7 g, with a 30% reduction being 14·0 g per day. We estimated that a 30% reduction in processed meat intake alone could lead to 352 900 (95% uncertainty interval 345 500-359 900) fewer occurrences of type 2 diabetes, 92 500 (85 600-99 900) fewer occurrences of cardiovascular disease, 53 300 (51 400-55 000) fewer occurrences of colorectal cancer, and 16 700 (15 300-17 700) fewer all-cause deaths during the 10-year period. A 30% reduction in unprocessed red meat intake alone could lead to 732 600 (725 700-740 400) fewer occurrences of type 2 diabetes, 291 500 (283 900-298 800) fewer occurrences of cardiovascular disease, 32 200 (31 500-32 700) fewer occurrences of colorectal cancer, and 46 100 (45 300-47 200) fewer all-cause deaths during the 10-year period. A 30% reduction in both processed meat and unprocessed red meat intake could lead to 1 073 400 (1 060 100-1 084 700) fewer occurrences of type 2 diabetes, 382 400 (372 100-391 000) fewer occurrences of cardiovascular disease, 84 400 (82 100-86 200) fewer occurrences of colorectal cancer, and 62 200 (60 600-64 400) fewer all-cause deaths during the 10-year period. Reductions in processed meat consumption could reduce the burden of some chronic diseases in the USA. However, more research is needed to increase certainty in the estimated effects of reducing unprocessed red meat consumption. The Wellcome Trust.

Health versus Disorder, Disease, and Death: Unvaccinated Persons Are Incommensurably Healthier than Vaccinated

Results from the 2019/2020 nationwide Control Group Survey of Unvaccinated Americans (CGS) show that those refusing vaccines are thriving while those accepting them are being injured and met with a multiplicity of grave injuries as well as sudden unexpected death. This survey quantified the long-term health risks of total vaccine avoidance against the health outcomes observed in the 99.74% vaccine-exposed American population. Based upon the sample sizes for the controls vs. the exposed population, the p-values and odds ratios evidence the astronomical odds against the innocence of vaccines as the actual cause of well over 90% of the disabling and life-threatening chronic conditions suffered by Americans. The true “controls” (calculated to represent 0.26% of the population in 2020) have established the baseline disease risk incurred by those without exposure to vaccination. The null hypothesis, that no significant difference would be found between vaccinated vs. unvaccinated persons in heart disease, diabetes, digestive disorders, eczema, asthma, allergies, developmental disabilities, birth defects, epilepsy, autism, ADHD, cancers, and arthritis, is rejected with overwhelming statistical confidence and power in every single contrast. Because 99.74% of the U.S. population is vaccine-exposed, published national disease rates invariably reflect the frequency of observed negative outcomes arising from exposure to vaccines. The Control Group comparison graphs lead to the inescapable conclusion, and near mathematical certainty, that vaccine exposure is the actual cause of the observed disparity in health outcomes between vaccinated and unvaccinated populations. Vaccines are NOT moving the population toward better health, as suggested by the World Health Organization and the US Department of Health & Human Services, but rather toward epidemic levels of lifelong debilitating chronic disorders.

What Helps Us Decide to Adopt an Intervention: Efficacy, Costs, or Both?

What Helps Us Decide to Adopt an Intervention: Efficacy, Costs, or Both?

Brentuximab Vedotin with Chemotherapy for Patients with Previously Untreated, Stage III/IV Classical Hodgkin Lymphoma: 5-Year Update of the ECHELON-1 Study

Brentuximab Vedotin with Chemotherapy for Patients with Previously Untreated, Stage III/IV Classical Hodgkin Lymphoma: 5-Year Update of the ECHELON-1 Study

Risk of systemic autoimmune diseases in gastric disease patients with proton pump inhibitor use: a nationwide cohort study in Taiwan.

The risk factors for systemic autoimmune diseases (SAD) in gastric disease patients with proton pump inhibitor (PPI) use are still unclear. This study discussed this relationship in an Asian population. Patients without a prior history of SAD were identified from Taiwan's National Health Insurance Research Database between January 1, 2000, and December 31, 2010. Cox regression models were applied to estimate the hazard ratio (HR) with 95% confidence interval [CI] of SAD. The cumulative PPI dosage was stratified by quartiles of defined daily doses and adjusted for baseline disease risk score which served as the primary variables compared against no PPI use. We analyzed the data of 51,291 participants aged 18years or older and free of SAD at baseline. PPI users (n = 17,938) had a significantly increased risk of SAD over non-PPI users. There was a significantly higher risk of developing SAD in older age groups. A significant dose-dependent association was observed between cumulative PPI use and the risk of SAD. Female PPI users had significantly higher risk of developing SAD. In patients who received PPI, the autoimmune disease with significantly higher incidence was Sjögren syndrome (SjS) (adjusted HR [aHR] 1.82, 95% CI, 1.02-3.27) and rheumatoid arthritis (RA) (aHR, 2.19, 95% CI, 1.19-4.01). This study found PPI users to be associated with an increased risk of SAD. Older age or cumulative PPI use was significantly associated with SAD, and the highest incidence was SjS and RA among gastric disease patients who received PPI. Key Points • This nationwide long-term cohort study found PPI users to be associated with an increased risk of rheumatoid arthritis and Sjögren syndrome in Taiwan. • This finding may help with clinical risk evaluation and will inform further investigation of the pathogenesis between autoimmune diseases and PPI use.

Role of Racial, Demographic and Socioeconomic Disparities in Treatment Patterns and Outcomes in AML

Role of Racial, Demographic and Socioeconomic Disparities in Treatment Patterns and Outcomes in AML

Association of Diabetes and Glycated Hemoglobin With the Risk of Intracerebral Hemorrhage: A Population-Based Cohort Study

To examine the association of diabetes and glycated hemoglobin (HbA1c) with the risk of intracerebral hemorrhage (ICH) in a large population-based cohort. The computerized database of the largest health care provider in Israel was used to identify adult members aged 40 years or older and alive at 1 January 2010 (297,486 with diabetes and 1,167,585 without diabetes). The cohort was followed until 31 December 2017 for incidence of ICH. Multivariable Cox proportional hazards regression models, adjusted for baseline disease risk score, were applied to estimate the hazard ratio (HR) of ICH. Overall 4,170 ICH cases occurred during 10,730,915 person-years of follow-up. Diabetes was independently associated with increased ICH risk, with hazard ratio (HR) 1.36 (95% CI 1.27-1.45), and increased with longer diabetes duration: 1.23 (1.12-1.35) and 1.44 (1.34-1.56) for diabetes duration ≤5 years and >5 years, respectively. The increased ICH risk associated with diabetes was more pronounced in patients ≤60 years old (P interaction <0.001). Among patients with diabetes, HbA1c had a nonlinear J-shaped relationship with ICH (P for nonlinearity = 0.0186). Compared to the fourth HbA1c decile, 6.5-6.7% (48-50 mmol/mol), the HR for ICH was 1.27 (1.01-1.59) and 2.19 (1.75-2.73) in the lowest HbA1c decile, ≤6.0% (≤42 mmol/mol), and highest HbA1c decile, >9.3% (>78 mmol/mol), respectively. Diabetes is associated with increased risk of ICH that is directly associated with diabetes duration. ICH and HbA1c appear to have a J-shaped relationship, suggesting that both poor control as well as extreme intensive diabetes control might be associated with increased risk.

Association of statin use with spontaneous intracerebral hemorrhage: A cohort study.

To examine the association between statin exposure in a dose-dependent manner and intracerebral hemorrhage (ICH) in a large nationwide study. The computerized database of the largest health care provider in Israel was used to identify diagnosed ICH among new users of statins, who started statin treatment between 2005 and 2010. We assessed a dose-response relationship between ICH and statins, using the average atorvastatin equivalent daily dose (AAEDD). Multivariable Cox proportional hazard regression models, adjusted for baseline disease risk score, were applied to estimate the hazard ratio of ICH. Of the 345,531 included patients, 1,304 were diagnosed with ICH during a median follow-up of 9.5 years (interquartile range 7.6-11.0). Overall, 75.3% of patients had AAEDD <10 mg/d, 19.0% had AAEDD 0-19.9 mg/d, and 5.7% had AAEDD ≥20 mg/d. The corresponding proportions were 81.0%, 15.0%, 4.0% among ICH cases, and 75.3%, 19.0%, 5.7% among non-ICH cases. Compared to those with AAEDD <10 mg/d (reference), the adjusted hazard ratio (HR) for ICH was 0.68 (95% confidence interval [CI] 0.58-0.79) in those with AAEDD 10-19.9 mg/d, and 0.62 (0.47-0.81) in those with AAEDD ≥20 mg/d. Compared to the lowest baseline total cholesterol quartile, the adjusted HR for ICH was 0.71 (95% CI 0.62-0.82), 0.55 (0.47-0.64), and 0.57 (0.49-0.67) in those in the second, third, and highest quartiles, respectively. The results were similar and robust among highly persistent statin users and after controlling for the change in cholesterol level. This study confirms that the risk of ICH decreases with increasing cholesterol levels, but suggests that statin use might be associated with decreased risk of ICH.

Risk of dementia from proton pump inhibitor use in Asian population: A nationwide cohort study in Taiwan.

IntroductionConcerns have been raised regarding the potential association between proton pump inhibitor (PPI) use and dementia.ObjectiveThis study aimed to examine this association in an Asian population.MethodsPatients initiating PPI therapy between January 1, 2000 and December 31, 2003 without a prior history of dementia were identified from Taiwan’s National Health Insurance Research Database. The outcome of interest was all-cause dementia. Cox regression models were applied to estimate the hazard ratio (HR) of dementia. The cumulative PPI dosage stratified by quartiles of defined daily doses and adjusted for baseline disease risk score served as the primary variables compared against no PPI use.ResultsWe analyzed the data of 15726 participants aged 40 years or older and free of dementia at baseline. PPI users (n = 7863; average follow-up 8.44 years) had a significantly increased risk of dementia over non—PPI users (n = 7863; average follow-up 9.55 years) (adjusted HR [aHR] 1.22; 95% confidence interval: 1.05–1.42). A significant association was observed between cumulative PPI use and risk of dementia (P for trend = .013). Subgroup analysis showed excess frequency of dementia in PPI users diagnosed with depression (aHR 2.73 [1.91–3.89]), hyperlipidemia (aHR 1.81 [1.38–2.38]), ischemic heart disease (aHR 1.55 [1.12–2.14]), and hypertension (aHR 1.54 [1.21–1.95]).ConclusionsAn increased risk for dementia was identified among the Asian PPI users. Cumulative PPI use was significantly associated with dementia. Further investigation into the possible biological mechanisms underlying the relationship between dementia and PPI use is warranted.

Risk of Intracranial Hemorrhage From Statin Use in Asians: A Nationwide Cohort Study.

Reports of statin usage and increased risk of intracranial hemorrhage (ICH) have been inconsistent. This study examined potential associations between statin usage and the risk of ICH in subjects without a previous history of stroke. Patients initiating statin therapy between 2005 and 2009 without a previous history of ischemic or hemorrhagic stroke were identified from Taiwan's National Health Insurance database. Participants were stratified by advanced age (≥70 years), sex, and diagnosed hypertension. The outcome of interest was hospital admission for ICH (International Classification of Diseases, Ninth Revision, Clinical Modification codes 430, 431, 432). Cox regression models were applied to estimate the hazard ratio of ICH. The cumulative statin dosage stratified by quartile and adjusted for baseline disease risk score served as the primary variable using the lowest quartile of cumulative dosage as a reference. There were 1 096 547 statin initiators with an average follow-up of 3.3 years. The adjusted hazard ratio for ICH between the highest and the lowest quartile was nonsignificant at 1.06 with a 95% confidence interval spanning 1.00 (0.94-1.19). Similar nonsignificant results were found in sensitivity analyses using different outcome definitions or model adjustments, reinforcing the robustness of the study findings. Subgroup analysis identified an excess of ICH frequency in patients without diagnosed hypertension (adjusted hazard ratio 1.36 [1.11-1.67]). In general, no association was observed between cumulative statin use and the risk of ICH among subjects without a previous history of stroke. An increased risk was identified among the nonhypertensive cohort, but this finding should be interpreted with caution.

Modelling preventive effectiveness to estimate the equity tipping point: at what coverage can individual preventive interventions reduce socioeconomic disparities in diabetes risk?

Most individual preventive therapies potentially narrow or widen health disparities depending on the difference in community effectiveness across socioeconomic position (SEP). The equity tipping point (defined as the point at which health disparities become larger) can be calculated by varying components of community effectiveness such as baseline risk of disease, intervention coverage and/or intervention efficacy across SEP. We used a simple modelling approach to estimate the community effectiveness of diabetes prevention across SEP in Canada under different scenarios of intervention coverage. Five-year baseline diabetes risk differed between the lowest and highest income groups by 1.76%. Assuming complete coverage across all income groups, the difference was reduced to 0.90% (144 000 cases prevented) with lifestyle interventions and 1.24% (88 100 cases prevented) with pharmacotherapy. The equity tipping point was estimated to be a coverage difference of 30% for preventive interventions (100% and 70% coverage among the highest and lowest income earners, respectively). Disparities in diabetes risk could be measurably reduced if existing interventions were equally adopted across SEP. However, disparities in coverage could lead to increased inequity in risk. Simple modelling approaches can be used to examine the community effectiveness of individual preventive interventions and their potential to reduce (or increase) disparities. The equity tipping point can be used as a critical threshold for disparities analyses.

Continuation of statin therapy and a decreased risk of atrial fibrillation/flutter in patients with and without chronic kidney disease

BackgroundTo contain cost, Taiwan's previous National Health Insurance Reimbursement Policy requested that physicians discontinue their patients' statin therapy once the serum cholesterol had reached appropriate levels. This allowed us to evaluate the association between statin continuation and the occurrence of atrial fibrillation/flutter and whether it was modified by chronic kidney disease (CKD) status. MethodsPatients who initiated statin therapy between January 1, 2001 and December 31, 2009 were identified from a random sample of one million subjects in the Taiwan National Health Insurance Research Database. The outcome was atrial fibrillation/flutter. A proportional hazard regression model with time-varying statin use was applied to estimate the hazard ratios (HR) and 95% confidence intervals (CIs) for atrial fibrillation/flutter according to current statin use versus treatment discontinuation, adjusted for baseline disease risk scores and time-varying covariates. ResultsA total of 6767 CKD and 63,678 non-CKD patients initiating statin therapy were included and followed for an average of 4.0 years. A total of 1118 participants experienced new-onset atrial fibrillation/flutter. The incidence of atrial fibrillation/flutter was approximately 2 fold higher in the CKD patients. Continuation of statin therapy was associated with a 22% (adjusted hazard ratio 0.78; 95% CI: 0.65–0.93) and 57% (adjusted HR 0.43; 95% CI: 0.27–0.68) decrease in atrial fibrillation/flutter hazard as compared with discontinuation in non-CKD and CKD patients, respectively. ConclusionsContinuation of statin therapy was associated with a decreased risk of atrial fibrillation/flutter among CKD and non-CKD patients. However, further randomized studies are still needed to assess the association.

Environmental Factors in Multiple Sclerosis: Epstein‐Barr Virus, Vitamin D, and Cigarette Smoking

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. Although its cause is not known, genetic and environmental factors both influence susceptibility to the disease. From the large array of environmental risk factors that have been examined over the past century, infection with Epstein-Barr virus, ultraviolet light exposure/vitamin D status, and cigarette smoking stand out because of the strength of supporting evidence. Epstein-Barr virus infection early in life appears to be necessary permissive step for disease development and probably acts in adolescence and early adulthood. Vitamin D-related mechanisms and cigarette smoking probably modify baseline disease risk and could plausibly do so at several stages of life; smoking appears to negatively affect disease course. This review summarizes current evidence for these 3 putative multiple sclerosis risk factors and early attempts to develop risk models and examine gene-environment interactions for this complex disease.

How to apply results from randomized trials and systematic reviews to individual patient care

A clinician may apply the results from randomized controlled trials and population-based cohort studies to the management of an individual patient to determine whether the patient will achieve more benefit than harm from the intervention. From the data the clinician should determine what are the benefits and harms of the intervention, whether there are any variations in the relative treatment effect, whether the treatment effect varies with different baseline risks of disease in untreated patients, what are the predicted reductions in absolute risk of disease for individuals and whether the benefits outweigh the risks for their patient. If the patient is at a low risk of the outcome, the harms of therapy may not justify its use to prevent or treat the disease. However, if the patient is at a high risk of developing the outcome, he or she is likely to gain more benefit than harm from the therapy.

Evaluating Bias due to Population Stratification in Epidemiologic Studies of Gene-Gene or Gene-Environment Interactions

Confounding by ethnicity (i.e. population stratification) can result in bias and incorrect inferences in genotype-disease association studies, but the effect of population stratification in gene-gene or gene-environment interaction studies has not been addressed. We used logistic regression models to fit multiplicative interactions between two dichotomous variables that represented genetic and/or environmental factors for a binary disease outcome in a hypothetical cohort of multiple ethnicities. Biases in main effects and interactions due to population stratification were evaluated by comparing regression coefficients in mis-specified models that ignored ethnicities with their counterparts in models that accounted for ethnicities. We showed that biases in main effects and interactions were constrained by the differences in disease risks across the ethnicities. Therefore, large biases due to population stratification are not possible when baseline disease risk differences among ethnicities are small or moderate. Numerical examples of biases in genotype-genotype and/or genotype-environment interactions suggested that biases due to population stratification for main effects were generally small but could become large for studies of interactions, particularly when strong linkage disequilibrium between genes or large correlations between genetic and environmental factors existed. However, when linkage disequilibrium among genes or correlations among genes and environments were small, biases to main effects or interaction odds ratios were small to nonexistent.

Further development of the case-only design for assessing gene-environment interaction: evaluation of and adjustment for bias.

The case-only study for investigating gene-environment interactions provides increased statistical efficiency over case-control analyses. This design has been criticized for being susceptible to bias arising from non-independence between the genetic and environmental factors in the population. Given that independence is critical to the validity of case-only estimates of interaction, researchers frequently use controls to evaluate whether the independence assumption is tenable, as advised in the literature. Our work investigates to what extent this approach is appropriate and how non-independence can be accounted for in case-only analyses. We provide a formula in epidemiological terms that illustrates the relationship between the gene-environment association measured among controls and the gene-environment association in the source population. Using this formula, we conducted sensitivity analyses to describe the circumstances in which controls can be used as proxy for the source population when evaluating gene-environment independence. Lastly, we generated hypothetical cohort data to examine whether multivariable modelling approaches can be used to control for non-independence. Our sensitivity analyses show that controls should not be used to evaluate gene-environment independence in the population, even when the baseline risk of disease is low (i.e. 1%), and the interaction and independent effects are moderate (i.e. risk ratio = 2). When the factors are associated, it is possible to remove bias arising from non-independence using standard statistical multivariable techniques in case-only analyses. Even when the disease risk is low, evaluation of gene-environment independence in controls does not provide a consistent test for bias in the case-only study. Given that control for non-independence is possible when the source of the non-independence can be conceptualized, the case-only design may still be a useful epidemiological tool for examining gene-environment interactions.