Bayesian Imputation of Missing Covariates

Missing values are a pervasive problem in almost all kinds of studies. In large cohort studies, the type of study most often conducted in the field of epidemiology, missing observations in covariates pose the major challenge. Since measurements are taken in an uncontrolled environment, typically many covariates need to be considered as potential confounders to filter out unwanted influences that environmental factors may have on the estimates of interest. Due to the large number of variables measured and the fact that measurement often relies on participants recalling and reporting detailed information, large proportions of missing data are common in these types of studies. In light of the above, the research that forms this thesis focuses on the analysis of incomplete cohort study data where missingness is in the covariates. We describe a fully Bayesian approach to analyse and impute data in this setting and discuss a number of naive and more sophisticated approaches to impute such data using multiple imputation with chained equations (MICE). The fully Bayesian approach is applied to multiple applications from the field of Epidemiology, and is further extended to settings with time-varying covariates, in which additional challenges, such as the functional form of the association between outcome and covariate and potential endogeneity arise. Moreover, the implementation of the fully Bayesian approach in the R package JointAI is described and illustrated by mean

Bayesian imputation of time-varying covariates in linear mixed models

Studies involving large observational datasets commonly face the challenge of dealing with multiple missing values. The most popular approach to overcome this challenge, multiple imputation using chained equations, however, has been shown to be sub-optimal in complex settings, specifically in settings with longitudinal outcomes, which cannot be easily and adequately included in the imputation models. Bayesian methods avoid this difficulty by specification of a joint distribution and thus offer an alternative. A popular choice for that joint distribution is the multivariate normal distribution. In more complicated settings, as in our two motivating examples that involve time-varying covariates, additional issues require consideration: the endo- or exogeneity of the covariate and its functional relation with the outcome. In such situations, the implied assumptions of standard methods may be violated, resulting in bias. In this work, we extend and study a more flexible, Bayesian alternative to the multivariate normal approach, to better handle complex incomplete longitudinal data. We discuss and compare assumptions of the two Bayesian approaches about the endo- or exogeneity of the covariates and the functional form of the association with the outcome, and illustrate and evaluate consequences of violations of those assumptions using simulation studies and two real data examples

Dietary patterns in an elderly population and their relation with bone mineral density: the Rotterdam Study

Purpose: Our aim was to identify dietary patterns that are associated with bone mineral density (BMD) against a background of relatively high dairy intake in elderly Dutch subjects. Methods: Participants were 55 years of age and older (n = 5144) who were enrolled in The Rotterdam Study, a population-based prospective cohort study. Baseline intake of 28 pre-defined food groups was determined using a validated food frequency questionnaire. Dietary patterns were identified using principal component analysis. BMD was measured using dual-energy X-ray absorptiometry at baseline and at three subsequent visits (between 1993 and 2004). Linear mixed modelling was used to longitudinally analyse associations of adherence to each pattern with repeatedly measured BMD (both in Z scores). Results: After adjustment for confounders, two dietary patterns were associated with high BMD: a “Traditional” pattern, characterized by high intake of potatoes, meat and fat (β = 0.06; 95 % CI 0.03, 0.09) and a “Health conscious” pattern, characterized by high intake of fruits, vegetables, poultry and fish (β = 0.06; 95 % CI 0.04, 0.08). The “Processed” pattern, characterized by high intake of processed meat and alcohol, was associated with low BMD (β = −0.03; 95 % CI −0.06, −0.01). Associations of adherence to the “Health conscious” and “Processed” pattern with BMD were independent of body weight and height, whereas the association between adherence to the “Traditional” pattern with BMD was not. Conclusions: Against a background of high dairy intake and independent of anthropometrics, a “Health conscious” dietary pattern may have benefits for BMD, whereas a “Processed” dietary pattern may pose a risk for low BMD

Adherence to a plant-based, high-fibre dietary pattern is related to regression of non-alcoholic fatty liver disease in an elderly population

Dietary lifestyle intervention is key in treating non-alcoholic fatty liver disease (NAFLD). We aimed to examine the longitudinal relation between well-established dietary patterns as well as population-specific dietary patterns and NAFLD. Participants from two subsequent visits of the Rotterdam Study were included. All underwent serial abdominal ultrasonography (median follow-up: 4.4 years) and filled in a food frequency questionnaire. Secondary causes of steatosis were excluded. Dietary data from 389 items were collapsed into 28 food groups and a posteriori dietary patterns were identified using factor analysis. Additionally, we scored three a priori dietary patterns (Mediterranean Diet Score, Dutch Dietary Guidelines and WHO-score). Logistic mixed regression models were used to examine the relation between dietary patterns and NAFLD. Analyses were adjusted for demographic, lifestyle and metabolic factors. We included 963 participants of whom 343 had NAFLD. Follow-up data was available in 737 participants. Incident NAFLD was 5% and regressed NAFLD was 30%. We identified five a posteriori dietary patterns (cumulative explained variation [R2] = 20%). The patterns were characterised as: vegetable and fish, red meat and alcohol, traditional, salty snacks and sauces, high fat dairy & refined grains pattern. Adherence to the traditional pattern (i.e. high intake of vegetable oils/stanols, margarines/butters, potatoes, whole grains and sweets/desserts) was associated with regression of NAFLD per SD increase in Z-score (0.40, 95% CI 0.15–1.00). Adherence to the three a priori patterns all showed regression of NAFLD, but only the WHO-score showed a distinct association (0.73, 95% CI 0.53–1.00). Hence, in this large elderly population, adherence to a plant-based, high-fibre and low-fat diet was related to regression of NAFLD

A Priori and a Posteriori dietary patterns during pregnancy and gestational weight gain: The generation R study

Abnormal gestational weight gain (GWG) is associated with adverse pregnancy outcomes. We examined whether dietary patterns are associated with GWG. Participants included 3374 pregnant women from a population-based cohort in the Netherlands. Dietary intake during pregnancy was assessed with food-frequency questionnaires. Three a posteriori-derived dietary patterns were identified using principal component analysis: a “Vegetable, oil and fish”, a “Nuts, high-fiber cereals and soy”, and a “Margarine, sugar and snacks” pattern. The a priori-defined dietary pattern was based on national dietary recommendations. Weight was repeatedly measured around 13, 20 and 30 weeks of pregnancy; pre-pregnancy and maximum weight were self-reported. Normal weight women with high adherence to the “Vegetable, oil and fish” pattern had higher early-pregnancy GWG than those with low adherence (43 g/week (95% CI 16; 69) for highest vs. lowest quartile (Q)). Adherence to the “Margarine, sugar and snacks” pattern was associated with a higher prevalence of excessive GWG (OR 1.45 (95% CI 1.06; 1.99) Q4 vs. Q1). Normal weight women with higher scores on the “Nuts, high-fiber cereals and soy” pattern had more moderate GWG than women with lower scores (-0.01 (95% CI 0.02; -0.00) per SD). The a priori-defined pattern was not associated with GWG. To conclude, specific dietary patterns may play a role in early pregnancy but are not consistently associated with GWG

Microbiology and antibiotic susceptibility patterns in spontaneous bacterial peritonitis: A study of two Dutch cohorts at a 10-year interval

Background: Recent investigations suggest an increasing prevalence of Gram-positive and antibiotic-resistant bacteria causing spontaneous bacterial peritonitis (SBP), probably related to changes in antibiotic prescription patterns, in particular more widespread and long-term use of antibiotic prophylaxis with quinolones. Objective: The primary objective of this study was to assess potential changes in the microbiology of SBP in two patient cohorts studied at a 10-year interval. Further aims were to study prognostic factors and outcome of SBP. Methods: A retrospective double-cohort study, including all ascitic cultures from patients with cirrhosis obtained 2003–2005 and 2013–2014, was conducted. Results: In total 312 patients were included, 125 patients in the first and 187 patients in the second cohort. SBP was diagnosed in 132 of 840 analyzed ascitic fluid samples; 62 samples were culture positive. An increase of Gram-positive bacterial isolates was noted from 26% to 46% between cohorts (p = 0.122). The prevalence of multidrug-antibiotic–resistant pathogens increased from 25% to 32% (p = 0.350). Survival after SBP among the two cohorts was comparable. Conclusion: This single-center study in the Netherlands found a modest but nonsignificant increase in the proportion of patients with SBP caused by Gram-positive bacteria and multidrug-antibiotic–resistant bacteria over a 10-year period. Our findings differ from reported data in other countries and suggest empiric antibiotic prophylaxis and treatment of SBP should be based on national and regional microbiological findings and resistance patterns

The efficacy and safety of rifaximin-α: a 2-year observational study of overt hepatic encephalopathy

Background: After 5 years since the registration of rifaximin-α as a secondary prophylaxis for overt hepatic encephalopathy (HE) in the Netherlands, we aimed to evaluate the use of hospital resources and safety of rifaximin-α treatment in a real-world setting. Methods: We carried out prospective identification of all patients using rifaximin-α for overt HE. We assessed hospital resource use, bacterial infections, and adverse events during 6-month episodes before and after rifaximin-α initiation. Results: During 26 months we included 127 patients [71.7% male; median age 60.8 years (interquartile range: 56.2–66.1); median model for end-stage liver disease (MELD) score 15.0 (interq

Decline of ovarian function in patients with rheumatoid arthritis: serum anti-Mullerian hormone levels in a longitudinal cohort

Objective Rheumatoid arthritis (RA) often affects women in their fertile age, and is known to compromise female fertility. Serum anti-Müllerian hormone (AMH) levels are a proxy for the total number of primordial follicles, and a reliable predictor of the age at menopause. Our objective was to study the longitudinal intra-individual decline of serum AMH levels in female RA patients. Methods Female RA patients from a nationwide prospective cohort (2002–2008) were re-assess

Eczema phenotypes and risk of allergic and respiratory conditions in school age children

Background: Eczema phenotypes based on eczema onset and persistence might better identify groups prone to allergic and respiratory conditions than a binary definition of eczema. We examined the associations of childhood eczema phenotypes with allergic sensitization, allergy, asthma and lung function at school age. Methods: This study among 4277 children was embedded in a multi-ethnic population-based prospective cohort study. Five eczema phenotypes (never, early transient, mid-transient, late transient, persistent) based on parental-reported physician-diagnosed eczema from age 6 months until 10 years were identified. At age 10 years, allergic sensitization was measured by skin prick tests, physician-diagnosed allergy and asthma by parent-reported questionnaires, and lung function by spirometry. Adjusted linear, logistic and multinomial regression models were applied. Results: Compared with never eczema, all eczema phenotypes were associated with increased risks of asthma (odds ratios (OR) range (95% confidence interval): 2.68 (1.58, 4.57) to 11.53 (6.65, 20.01)), food and inhalant allergic sensitization (1.72 (1.25, 2.36) to 12.64 (7.20, 22.18)), and physician-diagnosed inhalant allergy (1.92 (1.34, 2.74) to 11.91 (7.52, 18.86)). Strongest effect estimates were observed of early and persistent eczema with the risk of physician-diagnosed food allergy (OR 6.95 (3.76, 12.84) and 35.05 (18.33, 70.00), respectively) and combined asthma and physician-diagnosed allergy (7.11 (4.33, 11.67) and 29.03 (15.27, 55.22), respectively). Eczema phenotypes were not associated with lung function measures. Conclusion: Eczema phenotypes were differentially associated with risks of respiratory and allergic conditions in school-aged children. Children with early transient and persistent eczema might benefit from more intense follow-up for early identification and treatment of asthma and allergies

Fecal calprotectin is an early predictor of endoscopic response and histologic remission after the start of vedolizumab in inflammatory bowel disease

Background and aims: Early prediction of the effect of vedolizumab (VDZ) in inflammatory bowel disease (IBD) is of paramount importance to guide clinical decisions. This study assessed whether early fecal calprotectin (FC) can predict endoscopic response and histologic remission after VDZ initiation. Methods: This was a prospective study. Inclusion criteria were endoscopic inflammation and FC >100 µg/g. FC was determined at baseline and weeks 2, 4, 8 and 16. At week 16, endoscopies with ileal and colonic biopsies were performed. FC changes were assessed with Wilcoxon Rank Sum tests. ROC statistics were used to assess the diagnostic accuracy of FC. Results: In total, 45 patients [27 Crohn’s disease (CD), 16/2 ulcerative colitis (UC)/IBD-unclassified] [40% males, median age 39 (28–51) years] were included. Week 16 endoscopic response and histologic remission rates were 58% and 33%. A median 37% decline in FC at week 2 was observed only in endoscopic responders, p = 0.025. FC <250 µg/g at week 8 predicted endoscopic response in both UC and CD (positive predictive value 100%), whereas absence of FC decline at week 8 corresponded with absence of endoscopic response in CD [negative predictive value (NPV) 82%] and absence of histologic remission in both UC and CD (NPV 90%). Conclusion: The onset of a decline in FC as early as week 2 is associated with endoscopic response to VDZ induction. FC <250 µg/g at week 8 is associated with endoscopic response, whereas absence of FC decline at week 8 is associated with absence of both endoscopic response and histologic remission. FC levels 8 weeks after the start of VDZ could be used to guide clinical decisions and might substitute for endoscopic response evaluation