Efficient design and analysis of extended case-control studies

The nested case-control design is widely used in epidemiology for its efficiency, as it combines the advantages of both cohort and case-control designs. This design is an extension of the matched case-control design, where the matching variable is the time of occurrence of the outcome. Consequently, the nested case-control data are usually analysed with conditional logistic regression; however, this analysis suffers from various limitations. Several authors have developed novel statistical methods for alternative analyses of nested case-control data using basic information from the underlying cohort. Among these methods, one approach consists of ignoring the matching, weighting the sampled individuals to recover a representation of the underlying cohort and analysing the data by maximising a weighted partial likelihood. This method can be considered when two conditions are fulfilled: 1) the sampling was performed in a well-defined underlying cohort for which basic information is available, and 2) the exact sampling procedure is known. This thesis aimed to refine and extend the scope of the weighted likelihood approach in nested case-control data analysis by investigating the advantages of this method as an alternative to the traditional conditional logistic regression in several situations. The reuse of nested case-control data to address a research question regarding a new outcome, the calculation of absolute risk, the mitigation of the problem of overmatching, the maximisation of the data exploitation in case of clustered data and the analysis of subgroups of nested case-control data were addressed in this thesis. While Studies I and III were motivated by an actual epidemiological question for which data were available, simulation studies were the main approach used in Studies II and IV. Reusing nested case-control data to address a research question regarding another outcome was the central point of interest in Study I. Addressing an epidemiological question regarding the risk factors for contralateral breast cancer, for which data on contralateral breast cancer case patients were available, the feasibility of reusing nested case-control data from a previous study as the control dataset was studied. Practical aspects of the approach were highlighted, such as the consequences of reusing data which have narrow inclusion criteria, the restriction in the choice of the type of weights which can be calculated and the importance of having information on censoring dates for controls. In addition, we found that an imperfect reconstruction of the study base led to similar estimates in the analysis compared to an appropriate study base reconstruction; moreover, we confirmed that using unstratified weights (in cases of stratified sampling) provided similar exposure estimates than stratified weights, provided that adjustments were made on the confounder variables which drove the sampling. We also confirmed that using a naïve unweighted method instead of an appropriate method led to biased estimates. Absolute risk estimation was studied in Study II. Two methods were compared with both simulation studies and a real data application. The ability of each method to provide valid absolute risk estimates was investigated, in particular in cases of matched study designs. Both the Langholz-Borgan and weighted methods provided valid estimates in most situations, the latter showing slightly higher levels of precision than the former. In case of fine matching, the Langholz-Borgan method was more prone to be biased than the weighted method and had larger standard errors. In Study III, we handled nested case-control data, which had been collected to address an epidemiological question regarding how radiation therapy and smoking interact in their association with lung cancer in female breast cancer patients. Data on paired organs (breast and lungs) were collected for exposure and outcome variables, which provided clustered data at the individual level. The collected data was also characterised by the problem of overmatching which arose at the design stage. Using weighted partial likelihood allowed mitigation of the problem of overmatching and better exploited the collected data, compared to conditional logistic regression. In addition, a further advantage of the weighted approach was to enable calculating the absolute risk for a lung to develop cancer given the radiation therapy dose received for breast cancer treatment and the smoking habits of the patient. In Study IV, we compared the conditional logistic regression and weighted likelihood methods in terms of validity and efficiency of nested case-control data subgroup analyses, with subgroups defined by different variables measured at baseline. All investigated subgroup analyses provided valid estimates with both analyses. The advantages of weighted likelihood compared to conditional logistic regression were highlighted for the estimate’s precision. In addition, we showed that the weighting system enabled, on average, the reconstruction of the correct number of individuals at risk over time, for the whole cohort and in subgroups. In conclusion, the weighted likelihood approach showed several advantages compared to the traditional conditional logistic regression in nested case-control data analysis, which reinforces, refines and extends what has been previously shown in the literature

Does autoimmune thyroid disease affects rheumatoid arthritis disease activity or response to methotrexate?

Publisher's version (útgefin grein)Objective: To investigate if autoimmune thyroid disease (AITD) impacts rheumatoid arthritis (RA) disease activity or response to methotrexate. Methods A nationwide register-based cohort study of 9 004 patients with new-onset RA from the Swedish Rheumatology Quality Register year 2006-2016, with linkage to other nationwide registers to identify comorbidity with AITD defined as thyroxine prescription before RA diagnosis, excluding non-autoimmune causes. We compared RA disease activity using 28-joint Disease Activity Score (DAS28) and its components, and EULAR response, between patients with and without AITD, using logistic regression. Results At diagnosis, patient reported outcome measures (PROMs; patient global, Health Assessment Questionnaire Disability Index and pain) but not objective disease activity measures (erythrocyte sedimentation rate and swollen joint count) were significantly higher (p<0.05 for all PROMs) among RA patients with AITD compared with those without. The level of DAS28 was 5.2 vs 5.1. By contrast, AITD had little influence on EULAR response to methotrexate at 3 months (OR of non/moderate response=0.95, 95% CI 0.8 to 1.1), nor at 6 months. When stratified by age, however, AITD was more common among EULAR non/moderate responders at 3 and 6 months in patients below 45 years resulting in ORs of non/moderate response of 1.44 (0.76-2.76) and 2.75 (1.04-7.28). Conclusion At diagnosis, RA patients with concomitant AITD score worse on patient reported but not on objective RA disease activity measures, while DAS28 was only marginally elevated. The overall chance of achieving a EULAR good response at 3 or 6 months remains unaffected, although among a limited subgroup of younger patients, AITD may be a predictor for an inferior primary response. © Author(s) (or their employer(s))This work was supported by research grants from the Swedish Research Council, the Swedish Cancer Society, the Swedish HeartLung Foundation, Nordforsk, Vinnova and FOREUM. Financial support information: Dr Askling has acted or acts as PI in agreements between Karolinska Institutet and the following entities, mainly related to the safety monitoring of immunomodulators in rheumatology: Abbvie, BMS, Eli Lilly, Merck, Pfizer, Roche, Samsung Bioepis, Sanofi.Peer Reviewe

Does persistence to methotrexate treatment in early rheumatoid arthritis have a familial component?

Funding Information: Open access funding provided by Karolinska Institute. HW received support for the project from Stiftelsen Anna och Emil Olssons fond, Reumatikerförbundet [grant no R-940868]; Stiftelsen Professor Nanna Svartz Fond [grant no 2020-00334]; Kung Gustav V:s 80 year foundation [grant no FAI-2020-0666]; Karolinska Institutet foundations [grant no 2020-02508 and 2020-02398]. TF and SS were supported by the Swedish Research Council [DNR 2016-01355 and DNR 2018-02803, respectively]. JA was supported by the Swedish Research Council; Nordforsk; Vinnova; Region Stockholm/Karolinska Institutet Funds (ALF) and the Swedish Heart Lung Foundation. Publisher Copyright: © 2022, The Author(s).Objectives: To assess whether persistence to treatment with methotrexate (MTX) in early rheumatoid arthritis (RA) is shared among first-degree relatives with RA and to estimate any underlying heritability. Methods: First-degree relative pairs diagnosed with RA 1999–2018 and starting MTX (in monotherapy) as their first disease-modifying anti-rheumatic drug (DMARD) treatment were identified by linking the Swedish Rheumatology Quality Register to national registers. Short- and long-term persistence to MTX was defined as remaining on treatment at 1 and 3 years, respectively, with no additional DMARDs added. We assessed familial aggregation through relative risks (RR) using log-binomial regression with robust standard errors and estimated heritability using tetrachoric correlations. We also explored the familial aggregation of EULAR treatment response after 3 and 6 months. To mimic the clinical setting, we also tested the association between having a family history of MTX persistence and persistence within the index patient. Results: Familial persistence was not associated with persistence at 1 (RR=1.02, 95% CI 0.87–1.20), only at 3 (RR=1.41, 95% CI 1.14–1.74) years. Heritability at 1 and 3 years was estimated to be 0.08 (95% CI 0–0.43) and 0.58 (95% CI 0.27–0.89), respectively. No significant associations were found between family history and EULAR response at 3 and 6 months, neither overall nor in the clinical setting analysis. Conclusions: Our findings imply a familial component, including a possible genetic element, within the long-term persistence to MTX following RA diagnosis. Whether this component is reflective of characteristics of the underlying RA disease or determinants for sustained response to MTX in itself will require further investigation.Peer reviewe

Biostatistique :Exercices pratiques

MED2, DENT2, VETE2, BIME2B, BIME2S, SAPU3G, SAPU3P, STAT088info:eu-repo/semantics/published

Biostatistique :Exercices pratiques

2e candidature Sciences médicales, 2e Candidature Sciences Biomédicales, 2e Candidature Sciences vétérinaires, 2e Candidature Science Dentaire - STAT 088info:eu-repo/semantics/published

Biostatistique :exercices pratiques

MED2, DENT2, VETE2, BIME2B, BIME2S, SAPU3G, SAPU3P - STAT088info:eu-repo/semantics/published

Biostatistique

SYL-9626 = Exercices pratiquesMED2, DENT2, VETE2, BIME2 - STAT-G-201/STAT-G-202/STAT-G-203info:eu-repo/semantics/published

Effectiveness and treatment retention of TNF inhibitors when used as monotherapy versus comedication with csDMARDs in 15 332 patients with psoriatic arthritis. Data from the EuroSpA collaboration

BACKGROUND Comedication with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) during treatment with tumour necrosis factor inhibitors (TNFi) is extensively used in psoriatic arthritis (PsA), although the additive benefit remains unclear. We aimed to compare treatment outcomes in patients with PsA treated with TNFi and csDMARD comedication versus TNFi monotherapy. METHODS Patients with PsA from 13 European countries who initiated a first TNFi in 2006-2017 were included. Country-specific comparisons of 1 year TNFi retention were performed by csDMARD comedication status, together with HRs for TNFi discontinuation (comedication vs monotherapy), adjusted for age, sex, calendar year, disease duration and Disease Activity Score with 28 joints (DAS28). Adjusted ORs of clinical remission (based on DAS28) at 12 months were calculated. Between-country heterogeneity was assessed using random-effect meta-analyses, combined results were presented when heterogeneity was not significant. Secondary analyses stratified according to TNFi subtype (adalimumab/infliximab/etanercept) and restricted to methotrexate as comedication were performed. RESULTS In total, 15 332 patients were included (62% comedication, 38% monotherapy). TNFi retention varied across countries, with significant heterogeneity precluding a combined estimate. Comedication was associated with better remission rates, pooled OR 1.25 (1.12-1.41). Methotrexate comedication was associated with improved remission for adalimumab (OR 1.45 (1.23-1.72)) and infliximab (OR 1.55 (1.21-1.98)) and improved retention for infliximab. No effect of comedication was demonstrated for etanercept. CONCLUSION This large observational study suggests that, as used in clinical practice, csDMARD and TNFi comedication are associated with improved remission rates, and specifically, comedication with methotrexate increases remission rates for both adalimumab and infliximab

Comparative cardiovascular safety with janus kinase inhibitors and biological disease-modifying antirheumatic drugs as used in clinical practice: an observational cohort study from Sweden in patients with rheumatoid arthritis

Objectives To compare the incidence of cardiovascular (CV) events in rheumatoid arthritis (RA) treated with janus kinase inhibitors (JAKi), tumour necrosis factor inhibitors (TNFi), or other biological disease-modifying antirheumatic drugs (bDMARDs), in clinical practice, and to contextualise these findings by comparing to the Swedish RA population and general population at large.Methods Patients with RA initiating JAKi, TNFi and non-TNFi bDMARDs were identified in the Swedish Rheumatology Quality Register between 2016 and 2021. Through linkages to national registers, a cohort of patients with RA, general population comparators, as well as covariates and incident major acute CV event (MACE, including myocardial infarction, stroke and fatal CV events) were identified until 2022. Crude and age-sex standardised rates were calculated and HRs estimated from multivariable Cox regression models using TNFi as reference.Results We identified 13 492 patients with RA initiating a JAKi, non-TNFi bDMARD or TNFi treatment. Among 3037 JAKi-initiators, 59 MACE events were observed. The age-sex standardised rates for MACE were similar in the JAKi (0.88 per 100 person years) and TNFi (0.91) cohorts. Fully adjusted models showed no increased rate of MACE with JAKi (HR=0.71, 95% CI 0.51 to 0.99), or non-TNFi bDMARD (HR=0.98; 95% CI 0.78 to 1.23) in comparison to TNFi. We found no evidence that this HR changed over time since treatment initiation. In a CV-enriched subset, we observed higher rates but similar HRs.Conclusions As used in present clinical practice in Sweden, we found no evidence that CV risk is higher with JAKis than TNFis in RA

How does current disease activity in rheumatoid arthritis affect the short-term risk of acute coronary syndrome? : A clinical register based study from Sweden and Norway

Objectives: To estimate short-term risks of acute coronary syndrome (ACS) in patients with rheumatoid arthritis (RA) as a function of current RA disease activity including remission. Methods: Data from clinical visits of RA patients in Sweden (SE) and Norway (NO) between January 1st 2012 until December 31st 2020 were used. At each visit, patient's disease activity was assessed including remission status (measured with several metrics). Through linkage to national health and death registers, patients were followed up for incident ACS up to six months from each visit. We compared the short-term risk of ACS in patients not in remission vs. in remission using Cox regression analyses with robust standard errors, adjusted for country and covariates (e.g., age, sex, prednisolone use, comorbidities). We also explored disease activity categories as exposure. Results: We included 212,493 visits (10,444 from Norway and 202,049 from Sweden) among 41,250 patients (72% women, mean age at visit 62 years). During the 6-month follow-ups, we observed 524 incident ACS events. Compared to patients in remission, patients currently not in remission had an increased rate of ACS: adjusted hazard ratio (95% confidence interval) 1.52 (1.24–1.85) with DAS28 metric. The crude absolute six-month risks were 0.2% for patients in remission vs. 0.4% for patients with DAS28 high disease activity. The use of alternative RA disease activity and remission metrics provided similar results. Conclusion: Failure to reach remission is associated with elevated short-term risks of ACS, underscoring the need for CV risk factor optimization in these patients