Mitigating bias and dealing with multiple time scales in cohort studies : Studying medications and complications of diabetes

Cohort studies are an important and powerful tool of epidemiologic research. When based on a representative cohort, observational cohort studies provide results of a high external validity given that the internal validity is not impaired by bias. Diabetes and cancer represent two prevalent, complex, diverse and potentially fatal chronic diseases, occurs more often than could be expected by chance only. Cancer and diabetes share common risk factors, such as obesity and smoking, but also antidiabetic medications may play a role. I studied the relationship between the use of antidiabetic medications and cancer risk in two retrospectively conducted observational cohort studies, when mitigating bias through the study design and analytical methods. In Study I, I studied the risk of cancer in 23 394 individuals from the National FINRISK cohorts. I assessed the risk along time since the initiation of anti-diabetic medication and adjusted for several risk factors, including smoking and body mass index. I found no association between cancer risk and the use of antidiabetic medication. In Study II on the CARING (CAncer Risk and INsulin Analogues) five-country (Denmark, Finland, Norway, Sweden, UK) cohort of 327 112 new insulin users, the risks of ten site-specific cancers and any cancer were scrutinized by contrasting the cumulative exposures to human insulin and insulin analogues glargine and detemir, when mitigating biases involved in previous observational studies. We found no consistent differences in the studied risks as assessed for insulin glargine or insulin detemir use relative to use of human insulin. Due to their longitudinal nature, cohort studies involve at least one time scale at which the time-dependent dynamics of a phenomenon can be studied. There are often several relevant time scales, but the traditional statistical methods of survival analysis, such as Cox’s proportional hazards model, rely on a single time scale. In the methodological part of this thesis, I addressed the issue of multiple time scales. In Study III, I addressed the issue of multiple time scales in cohort studies by introducing and evaluating a nonparametric Bayesian model for estimation of intensity on two time scales jointly. Because of the built-in smoothing and borrowing of strength in two dimensions, the model outperformed two other methods when applied to simulated data. In Study IV, I used the Bayesian intensity model to explore the time-dependent dynamics of end-stage-renal-disease and death without end-stage-renal disease in 11 810 individuals with type 1 diabetes from the nation-wide FinDM study. The time-dependent dynamics of these outcomes were modelled on two and three time scales jointly, including age, diabetes duration and calendar time. The study demonstrated that the estimation of multidimensional hazard allows for addressing both empirical and methodological questions.Kohorttitutkimukset ovat epidemiologisen tutkimuksen tärkeä ja tehokas väline, jonka avulla valitussa populaatiossa tutkitaan altisteen vaikutusta sairauden ilmaantumiseen. Väestöön perustuvassa havainnoivassa kohorttitutkimuksessa saatujen tulosten ulkoinen luotettavuus on korkea edellyttäen, ettei sisäinen luotettavuus ole harhan heikentämä. Harha voi syntyä missä tahansa tutkimuksen vaiheessa ja on olemassa lukuisia harhan lähteitä, kuten valintaharha ja sekoittuneisuus. Harha voidaan kuitenkin estää tai vähentää oikeilla tutkimusmenetelmillä. Diabetes ja syöpä ovat kaksi yleistä, monimuotoista kroonista sairautta, jotka esiintyvät yhdessä henkilössä odotettua useammin. Syövällä ja diabeteksella on yhteisiä riskitekijöitä, kuten liikalihavuus ja tupakointi, mutta myös muut tekijät, kuten diabeteslääkkeiden käyttö, saattavat selittää diabeteksen ja syövän välistä yhteyttä. Tämän väitöskirjan empiirinen osa koostui kahdesta havainnoivasta lääke-epidemiologisesta kohorttitutkimuksesta, joissa tarkastelin retrospektiivisesti diabeteslääkkeiden käytön ja syöpäriskin välistä suhdetta. Harhaa pyrin välttämään / pienentämään asianmukaisella tutkimusasetelmalla ja analyyttisin menetelmin. Kansallisiin FINRISK-kohortteihin perustuvassa 23 394 henkilön tutkimuksessa ei tullut esiin mitään yhteyttä diabeteslääkkeiden käytön ja syöpäriskin välillä. Viiden maan (Tanska, Suomi, Norja, Ruotsi, Iso-Britannia) CARING (CAncer Risk and INsulin Analogues) rekisteripohjaisessa kohorttitutkimuksessa mukana oli 327 112 insuliinihoitoa aloittanutta henkilöä, joista 21 390 henkilössä todettiin syöpä seurannan aikana. Tässä toistaiseksi laajimmassa tutkimuksessa kokonaissyöpäriskissä ja kymmenen eri syöpätyypin riskissä ei havaittu johdonmukaista eroa insuliinianalogien (glargiini, detemiri) ja ihmisinsuliiniin välillä. Kohorttitutkimukset perustuvat seurantaan ja näin niihin liittyy vähintään yksi aikaskaala, jolla tutkitaan aikaa kiinnostuksen kohteena olevaan tapahtumaan. Perinteiset tilastomenetelmät perustuvat vain yhteen aikaskaalaan, mutta usein ilmiöön liittyy useita tärkeitä aikaskaaloja. Esimerkiksi diabeteksen pitkäaikaiskomplikaatioiden riski voi vaihdella iän, kalenteriajan ja diabeteksen keston mukaan. Tämän väitöskirjan menetelmällisessä osassa esitin parametrittoman Bayes-päättelyyn perustuvan mallin, jonka avulla voidaan arvioida riskiä kahdella tai useammalla aikaskaalalla. Bayes-mallilla tarkastelin ajasta riippuvaa loppuvaiheen munuaistaudin vaaran ja kuolleisuuden dynamiikkaa 11 810 tyypin 1 diabetesta sairastavan henkilön FinDM kohortissa. Tulosten perusteella dynamiikkaan vaikuttivat ikä, diabeteksen kesto ja kalenteriaika

Distinct age-related patterns of overweight development to guide school healthcare interventions

Aim We aimed to identify groups of primary school children with similar overweight development, reveal age-related patterns of overweight development in the resulting groups and analyse overweight-related school healthcare interventions. Methods This retrospective longitudinal register study utilised electronic health records from six primary school years. From a random sample of 2000 sixth graders, we derived a study cohort of 508 children meeting criteria for overweight at least once during primary school. We investigated how many different groups (latent classes) of children with similar weight development would emerge by applying flexible latent class mixed models on body mass index standard deviation score. We also explored the resulting groups with respect to offered overweight-related interventions. Results Per child, the data consisted in median 7 growth measurements over 5.4 years. We identified five overweight development groups for girls and four for boys. The groups converged temporarily around age 10 after which only some continued into obesity. School nurses and physicians offered overweight-related interventions to children with obesity, less to children gaining weight or with overweight. Conclusion Obesity prevention might benefit from awareness of typical overweight development patterns when designing intervention studies or planning and timing multidisciplinary school health check programmes.Peer reviewe

Periodontitis and cancer mortality : Register-based cohort study of 68,273 adults in 10-year follow-up

Periodontitis, a multifactorial infection-induced low-grade chronic inflammation, can influence the process of carcinogenesis. We studied with 10 years follow-up of 68,273 adults-based cohort the involvement of periodontitis as a risk factor for cancer mortality. Periodontal status was defined based on procedure codes of periodontal treatment. Rate ratios and absolute differences of overall and cancer mortality rates were assessed with respect to periodontal status using multiplicative and additive Poisson regression models, respectively. We adjusted for effect of age, sex, calendar time, socio-economic status, oral health, dental treatments and diabetes. Data about smoking or alcohol consumption were not available. Altogether 797 cancer deaths occurred during 664,020 person-years accumulated over a mean 10.1-year follow-up. Crude cancer mortality rate per 10,000 person-years for participants without and with periodontitis was 11.36 (95% CI 10.47-12.31) and 14.45 (95% CI 12.51-16.61), respectively. Crude rate ratios for periodontitis indicated an increased risk of overall (RR 1.27, 95% CI 1.08-1.39) and pancreatic cancer (RR 1.69, 95% CI 1.04-2.76) mortality. After adjustment, the results showed even stronger associations of periodontitis with increased overall (RR 1.33, 95% CI 1.10-1.58) and pancreatic cancer (RR 2.32, 95% CI 1.31-3.98) mortality. A higher pancreatic cancer mortality among individuals with periodontitis contributed considerably to the difference in overall cancer mortality, but this difference was not due to pancreatic cancer deaths alone. What's new? Periodontitis is characterized by infection-driven inflammation, a type of inflammation that is a factor in about 15% of human tumors. It remains unclear, however, whether periodontitis increases cancer risk or influences cancer mortality. In this study, long-term follow-up on a large cohort of dental patients in Finland suggests that periodontitis is associated with increased overall cancer mortality, especially increased mortality from pancreatic cancer. The findings suggest that the prevention and treatment of periodontitis can help reduce the risk of systemic adverse events, such as death, from cancer.Peer reviewe

Oral health associated with incident diabetes but not other chronic diseases: A register-based cohort study

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Predictors of choosing long-acting reversible contraceptive methods when provided free-of-charge - A prospective cohort study in Finland

Objective: To identify factors associated with choosing long-acting reversible contraception (LARC) (intrauterine device or contraceptive implant), when provided free-of-charge. Study design: This register-based cohort study comprises all women living in the city of Vantaa in the Helsinki metropolitan area during 2013-2014, with information on LARC initiations retrieved from electronic health records. Since January 2013, women in Vantaa can receive their first LARC method free-of-charge at public contraceptive clinics. We performed multivariable regression to assess seven predictors based on literature and four predictors based on gynecological history for association with choosing LARC in this population. Results: In 2013-2014, 9669 women entitled to a free-of-charge method visited a public clinic and 2035 (21.0%) women initiated LARC. Factors most associated with LARC initiation included history of delivery (odds ratio [OR] 5.4, 95% confidence intervals [CI] 4.7-6.2) and induced abortion (OR 1.4, 95%CI 1.2-1.6), and no previous visit at the clinic (OR 1.3, 95%CI 1.2-1.5). Previous delivery was associated with LARC initiation in all age-groups (OR, 95%CI by age-group; 15-19 years: 10.8, 5.1-23.4; 20-24 years: 6.4, 4.9-8.3; 25-29 years: 6.7, 5.2-8.6; 30-44 years: 3.6, 2.9-4.6). Conclusion: History of delivery and induced abortion were strongly associated with choosing a LARC method, even though all women in the population were entitled to their first free-of-charge LARC method. The association was particularly strong among women less than 25 years of age. Implications statement: Untargeted provision of free-of-charge LARC in public contraceptive services reached women with previous delivery or abortion well during the programs first years. However, as LARCs are recommended to all women, future research should focus on how uptake evolves and how to reach all women in need of long-term, effective contraception. (C) 2020 Elsevier Inc. All rights reserved.Peer reviewe

Systemic hormonal contraception and risk of venous thromboembolism

Introduction The increased risk of venous thromboembolism associated with the use of hormonal contraception is well recognized, but evidence regarding hormonal contraception containing natural estradiol is limited. This study aimed to assess the associations between the patterns of use of different systemic hormonal contraceptives and the risk of venous thromboembolism during 2017-2019. Material and Methods All fertile-aged women (15-49 years) living in Finland in 2017 and using hormonal contraception in 2017 and their 1:1 age- and residence-matched controls not using hormonal contraception in 2017 (altogether 587 559 women) were selected from the Prescription Centre. All incident venous thromboembolism cases during 2018-2019 and their 4:1 age-matched controls were further analyzed in a prospective nested case-control design to assess the associations between the use (starting, stopping, continuous vs no use) of different hormonal contraception types and venous thromboembolism. Results Altogether, 1334 venous thromboembolism cases occurred during the follow-up period (incidence rate 1.14 per 1000 person-years, 95% confidence interval [CI] 1.08-1.20), with an incidence rate ratio of hormonal contraception vs no hormonal contraception use of 1.42 (95% CI 1.27-1.58). Compared with non-use, starting the use of gestodene and ethinylestradiol (adjusted odds ratio [aOR] 2.85; 95% CI 1.62-5.03), drospirenone and ethinylestradiol (aOR 1.55; 95% CI 0.98-2.44), desogestrel and ethinylestradiol (aOR 1.97; 95% CI 0.99-3.92), and transdermal patch releasing norelgestromin and ethinylestradiol (aOR 5.10; 95% CI 1.12-23.16), as well as continuing the use of gestodene and ethinylestradiol (aOR 2.60; 95% CI 1.61-4.21), drospirenone and ethinylestradiol (aOR 1.55; 95% CI 1.02-2.37), cyproterone-acetate and estrogen/ethinylestradiol (aOR 1.66; 95% CI 1.06-2.61), and vaginal ring releasing etonogestrel and ethinylestradiol (aOR 3.27; 95% CI 1.95-5.48) were associated with venous thromboembolism risk. Regarding the type of estrogen, the highest risk was associated with current use (vs non use in the previous 180 days) of ethinylestradiol-containing preparations (aOR 2.20; 95% CI 1.82-2.65), followed by estradiol-containing preparations (aOR 1.39; 95% CI 1.04-1.87) with no risk for progestin-only hormonal contraception. Current use of estradiol-containing preparations was not associated with venous thromboembolism risk after exclusion of cyproterone-acetate and estrogen/ethinylestradiol (aOR 1.05; 95% CI 0.66-1.66). Conclusions An increased risk of venous thromboembolism is associated with ethinylestradiol-containing combined preparations. The use of estradiol-containing combined preparations confers only a slightly increased risk, possibly driven by cyproterone-containing combined oral contraceptives, whereas the use of progestin-only contraception is not associated with venous thromboembolism.Peer reviewe

Incidence of extraovarian clear cell cancers in women with surgically diagnosed endometriosis : A cohort study

Background Endometriosis is associated with increased risk of clear cell ovarian cancer and has even suggested being an etiological factor for this cancer. Association between endometriosis and extraovarian clear cell cancers is unclear. This study aimed to assess the association between surgically diagnosed endometriosis and risk of extraovarian clear cell cancers according to the type of endometriosis (i.e., ovarian, peritoneal, and other endometriosis) and the site of clear cell cancer. Methods In this register-based historic cohort study we identified all women with surgically diagnosed endometriosis from the Finnish Hospital Discharge Registry 1987-2012. Data on extraovarian clear cell cancers of these women were obtained from the Finnish Cancer Registry. The follow-up started January 1(st), 2007 or at endometriosis diagnosis (if later), and ended at emigration, death or on the December 31(st), 2014. Standardized incidence ratios were calculated for each site of clear cell carcinoma (intestine, kidney, urinary tract, gynecological organs other than ovary), using the Finnish female population as reference. Results The endometriosis cohort consisted of 48,996 women, including 22,745 women with ovarian and 19,809 women with peritoneal endometriosis. Altogether 23 extraovarian clear cell cancers were observed during 367,386 person-years of follow-up. The risk of extraovarian clear cell cancer was not increased among all women with surgically diagnosed endometriosis (standardized incidence ratio 0.89, 95% confidence interval 0.56-1.33) nor in different types of endometriosis. The incidence of clear cell cancer in any specific site was not increased either. Conclusions The risk of extraovarian clear cell cancers in women with surgically diagnosed endometriosis is similar to that in the general population in Finland.Peer reviewe

Population-level indicators associated with hormonal contraception use : a register-based matched case-control study

Background Monitoring factors related to hormonal contraception (HC) use is essential to evaluating public health strategies and promoting access to contraception. We aimed to examine municipal social and health indicators of HC use at the population level, and to identify patterns of inequality across Finnish municipalities. Methods We identified all women (15-49 years) with a redeemed HC prescription in Finland in 2017 (n = 294,445), and a control group of non-users. Municipal social and health indicators at the population level were retrieved from the nationwide Statistics and Indicator Bank. Differences between the groups across 309 municipalities were calculated, and associations of municipal-specific proportions of HC users with municipal-specific indicators were studied using LASSO (Least Absolute Shrinkage and Selection Operator) models. Results Sociodemographic differences between HC users and non-users were non-homogenous across municipalities. Indicators positively associated with HC use included: larger population and higher proportions of population aged 16-24 years, of household-dwelling units with one person, of persons with higher education, and of divorces among those aged 25-64. Lower HC use was associated with higher proportions of Swedish-speaking population, of those aged 7-15 years, of young people not in education/training, and of household-dwelling units in overcrowded conditions. Lower HC use was also associated with indicators of outpatient and inpatient healthcare, and of municipal finances in welfare and healthcare. Conclusions Sociodemographic differences in relation to HC use exist across Finnish municipalities. Municipal indicators of social structure, health and welfare, and investment in and use of healthcare services are related to HC use.Peer reviewe

Associations between hormonal contraception use, sociodemographic factors and mental health: a nationwide, register-based, matched case–control study

Objectives Sociodemographic and mental health characteristics are associated with contraceptive choices. We aimed to describe the sociodemographic, reproductive and mental health characteristics of all fertile-aged women in Finland who used hormonal contraception (HC) in 2017. Design A nationwide, register-based study. Setting All women living in Finland in 2017; data from the Care Register of Health Care, Medical Birth Register, Population Register Centre, Prescription Centre, Register of Induced Abortions. Participants All women aged 15-49 with one redeemed HC prescription in 2017 (n=294 356), and a same-sized, age-matched and residence-matched, control group of non-users. Outcomes Rates of HC use; associations between HC use and mental disorders, sociodemographic and reproductive characteristics. Results 25.8% of women aged 15-49 years used HC. Women with the lowest socioeconomic levels had lower odds of using HC than women with upper-level statuses (OR, 95% CI students: 0.97, 0.94 to 0.99; entitled to pension: 0.66, 0.63 to 0.69; other: 0.87, 0.85 to 0.89; unknown: 0.90, 0.85 to 0.90). Women with the highest education (secondary: 1.46, 1.43 to 1.48; tertiary: 1.64, 1.58 to 1.70; academic: 1.60, 1.56 to 1.63) and income (second quarter: 1.57, 1.54 to 1.60; third quarter: 1.85, 1.82 to 1.89; fourth quarter: 2.01, 1.97 to 2.06), and unmarried women had higher odds of using HC than women with the lowest education and income levels, and married (0.61, 0.60 to 0.62), divorced (0.86, 0.84 to 0.88), widowed (0.73, 0.65 to 0.83) or other marital status women (0.26, 0.22 to 0.30). Parous women (0.70, 0.69 to 0.71), those with previous induced abortion(s) (0.91, 0.89 to 0.92) or recent eating (0.68, 0.62 to 0.75) or personality (0.89, 0.79 to 0.97) disorders had lower odds of HC use. Absolute risk differences between women with and without mental disorders ranged from 3.1% (anxiety disorders) to 10.1% (eating disorders). Conclusions A quarter of the fertile-aged women use HC in Finland. Sociodemographic disparities persist in relation to HC use, although of small effect size. HC use is less common among women suffering from severe to moderate psychiatric disorders, especially eating disorders.Peer reviewe