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Family history of substance use disorder (SUD) affects a child's risk of the disorder through both genetic and shared environmental factors. We aimed to estimate the association between parental or older sibling SUD history with the risk of adolescent SUD diagnosis.We conducted a population-based cohort study using administrative health-care databases in the Province of Manitoba, Canada, which has a universal and publicly funded health-care system. We included all children born from 1984 to 2000 who have linkages to both parents and were followed until age 18 years. We used generalized estimating equation models to produce unadjusted and adjusted relative risk (RR) estimates of adolescent SUD risk. The study cohort included 134 389 children and 31 307 full sibling pairs; 51.3% were male and 35.4% first-born.The exposure was SUD diagnosis in a mother or father in either hospitalization or outpatient physician visit records before the children's age of 13 years. The secondary exposure was an adolescent SUD diagnosis in an older full sibling. The outcome was SUD diagnosis during adolescence (13 and 18 years of age) identified in either hospitalization or physician visit records. Children demographics and characteristics associated with SUD diagnosis were included in the models.Of the 134 389 children, 9.5% had a mother with a history of SUD, 11.3% had a father and 1.3% had an older sibling with a history of SUD diagnosis; 2566 (1.9%) had an adolescent SUD diagnosis. An increased risk of adolescent SUD was observed with SUD history in mothers [adjusted RR (aRR) = 2.50; 95% confidence interval (CI) = 2.26, 2.79], fathers (aRR = 2.15; 95% CI = 1.95, 2.37), both parents (aRR = 3.74; 95% CI = 3.24, 4.31) and older sibling (aRR = 3.85; 95% CI = 2.53, 5.87).A family history of substance use disorder in parents or older siblings appears to be associated with increased SUD risk in adolescents.

We investigated the association of objectively ascertained sibling fracture history with major osteoporotic fracture (hip, forearm, humerus, or clinical spine) risk in a population-based cohort using administrative databases. Sibling fracture history is associated with increased major osteoporotic fracture risk, which has implications for fracture risk prediction. We aimed to determine whether objectively ascertained sibling fracture history is associated with major osteoporotic fracture (MOF; hip, forearm, humerus, or clinical spine) risk. This retrospective cohort study used administrative databases from the province of Manitoba, Canada, which has a universal healthcare system. The cohort included men and women 40+ years between 1997 and 2015 with linkage to at least one sibling. The exposure was sibling MOF diagnosis occurring after age 40 years and prior to the outcome. The outcome was incident MOF identified in hospital and physician records using established case definitions. A multivariable Cox proportional hazards regression model was used to estimate the risk of MOF after adjustment for known fracture risk factors. The cohort included 217,527 individuals; 91.9% were linked to full siblings (siblings having the same father and mother) and 49.0% were females. By the end of the study period, 6255 (2.9%) of the siblings had a MOF. During a median follow-up of 11 years (IQR 5–15), 5235 (2.4%) incident MOF were identified in the study cohort, including 234 hip fractures. Sibling MOF history was associated with an increased risk of MOF (hazard ratio [HR] 1.67, 95% confidence interval [CI] 1.44–1.92). The risk was elevated in both men (HR 1.57, 95% CI 1.24–1.98) and women (HR 1.74, 95% CI 1.45–2.08). The highest risk was associated with a sibling diagnosis of forearm fracture (HR 1.81, 95% CI 1.53–2.15). Sibling fracture history is associated with increased MOF risk and should be considered as a candidate risk factor for improving fracture risk prediction.

BACKGROUND: Abnormal microbiota composition induced by prenatal exposure to antibiotics has been proposed as a potential contributor to the development of attention-deficit/hyperactivity disorder (ADHD). We examined the association between prenatal antibiotic exposure and risk of ADHD. METHODS: We conducted a population-based retrospective cohort study of children born in Manitoba, Canada, between 1998 and 2017 and their mothers. We defined exposure as the mother having filled 1 or more antibiotic prescriptions during pregnancy. The outcome was diagnosis of ADHD in the offspring, as identified in administrative databases. We estimated hazard ratios (HRs) using Cox proportional hazards regression in the overall cohort, in a separate cohort matched on high-dimensional propensity scores and in a sibling cohort. RESULTS: In the overall cohort, consisting of 187 605 children, prenatal antibiotic dispensation was associated with increased risk of ADHD (HR 1.22, 95% confidence interval [CI] 1.18–1.26). Similar results were observed in the matched cohort of 129 674 children (HR 1.20, 95% CI 1.15–1.24) but not in the sibling cohort (HR 1.06, 95% CI 0.99–1.13). Two negative-control analyses indicated a positive association with ADHD despite the lack of a reasonable biological mechanism, which suggested that the observed association between prenatal antibiotic dispensation and risk of ADHD was likely due to confounding. INTERPRETATION: In our study, prenatal antibiotic exposure was not associated with increased risk of ADHD in children. Although the risk was higher in the overall and matched cohorts, it was likely overestimated because of unmeasured confounding. Future studies are warranted to examine other factors affecting microbiota composition in association with risk of ADHD.

To highlight the potential of multiple file record linkage. Linkage increases the value of existing information by supplying missing data or correcting errors in existing data, through generating important covariates, and by using family information to control for unmeasured variables and expand research opportunities.Recent Manitoba papers highlight the use of linkage to produce better studies. Specific ways in which linkage helps deal with different substantive issues are described.Wide data files-files containing considerable amounts of information on each individual-generated by linkage improve research by facilitating better design. Nonexperimental work in particular benefits from such linkages. Population registries are especially valuable in supplying family data to facilitate work across different substantive fields.Several examples show how record linkage magnifies the value of information from individual projects. The results of observational studies become more defensible through the better designs facilitated by such linkage.

Background Diagnosis codes in administrative health data are routinely used to monitor trends in disease prevalence and incidence. The International Classification of Diseases (ICD), which is used to record these diagnoses, have been updated multiple times to reflect advances in health and medical research. Our objective was to examine the impact of transitions between ICD versions on the prevalence of chronic health conditions estimated from administrative health data. Methods Study data (i.e., physician billing claims, hospital records) were from the province of Manitoba, Canada, which has a universal healthcare system. ICDA-8 (with adaptations), ICD-9-CM (clinical modification), and ICD-10-CA (Canadian adaptation; hospital records only) codes are captured in the data. Annual study cohorts included all individuals 18 + years of age for 45 years from 1974 to 2018. Negative binomial regression was used to estimate annual age- and sex-adjusted prevalence and model parameters (i.e., slopes and intercepts) for 16 chronic health conditions. Statistical control charts were used to assess the impact of changes in ICD version on model parameter estimates. Hotelling’s T2 statistic was used to combine the parameter estimates and provide an out-of-control signal when its value was above a pre-specified control limit. Results The annual cohort sizes ranged from 360,341 to 824,816. Hypertension and skin cancer were among the most and least diagnosed health conditions, respectively; their prevalence per 1,000 population increased from 40.5 to 223.6 and from 0.3 to 2.1, respectively, within the study period. The average annual rate of change in prevalence ranged from -1.6% (95% confidence interval [CI]: -1.8, -1.4) for acute myocardial infarction to 14.6% (95% CI: 13.9, 15.2) for hypertension. The control chart indicated out-of-control observations when transitioning from ICDA-8 to ICD-9-CM for 75% of the investigated chronic health conditions but no out-of-control observations when transitioning from ICD-9-CM to ICD-10-CA. Conclusions The prevalence of most of the investigated chronic health conditions changed significantly in the transition from ICDA-8 to ICD-9-CM. These results point to the importance of considering changes in ICD coding as a factor that may influence the interpretation of trend estimates for chronic health conditions derived from administrative health data.

Family health history is a well-established risk factor for many health conditions but the systematic collection of health histories, particularly for multiple generations and multiple family members, can be challenging. Routinely-collected electronic databases in a select number of sites worldwide offer a powerful tool to conduct multigenerational health research for entire populations. At these sites, administrative and healthcare records are used to construct familial relationships and objectively-measured health histories. We review and synthesize published literature to compare the attributes of routinely-collected, linked databases for three European sites (Denmark, Norway, Sweden) and three non-European sites (Canadian province of Manitoba, Taiwan, Australian state of Western Australia) with the capability to conduct population-based multigenerational health research. Our review found that European sites primarily identified family structures using population registries, whereas non-European sites used health insurance registries (Manitoba and Taiwan) or linked data from multiple sources (Western Australia). Information on familial status was reported to be available as early as 1947 (Sweden); Taiwan had the fewest years of data available (1995 onwards). All centres reported near complete coverage of familial relationships for their population catchment regions. Challenges in working with these data include differentiating biological and legal relationships, establishing accurate familial linkages over time, and accurately identifying health conditions. This review provides important insights about the benefits and challenges of using routinely-collected, population-based linked databases for conducting population-based multigenerational health research, and identifies opportunities for future research within and across the data-intensive environments at these six sites.

OBJECTIVES: Autism spectrum disorders (ASD) are among the leading causes of disabilities in children. We examined the annual prevalence and incidence rate of ASD between 2004 and 2015 in children aged 1 to 5 years residing in Manitoba. METHODS: A population-based study was conducted using the Manitoba Population Research Data Repository. The study included children aged 1 to 5 years residing in Manitoba between 2004 and 2015. Standard identification algorithm was used to identify ASD cases from hospital abstracts and medical claims. Annual prevalence and incidence rates were calculated for the overall population and then stratified according to sex, region, and socio-economic status (SES). Multivariable negative binomial regression models, adjusted for sex, region, and SES, were used to examine changes in prevalence and incidence over study years. RESULTS: Among children aged 1 to 5 years, 1685 ASD cases were diagnosed between 2004 and 2015. The crude ASD prevalence increased from 0.46% in 2004 to 0.97% in 2015 (p = 0.002). The crude incidence rate increased from 0.16% in 2004 to 0.39% in 2015 (p = 0.002). The increase in ASD prevalence and incidence was observed in all subgroups based on sex, region, and SES. The adjusted negative binomial model showed an annual relative risk increase, since 2004, for both prevalence and incidence of 1.69 (95% CI 1.56–1.83) and 1.84 (95% CI 1.62–2.09), respectively. CONCLUSION: During the period from 2004 to 2015, both prevalence and incidence rates of diagnosed ASD in preschoolers and toddlers residing in Manitoba increased significantly. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.17269/s41997-019-00181-9) contains supplementary material, which is available to authorized users.

IntroductionAdministrative health data capture diagnoses using the International Classification of Diseases (ICD), which has multiple versions over time. To facilitate longitudinal investigations using these data, we aimed to map diagnoses identified in three ICD versions – ICD-8 with adaptations (ICDA-8), ICD-9 with clinical modifications (ICD-9-CM), and ICD-10 with Canadian adaptations (ICD-10-CA) – to mutually exclusive chronic health condition categories adapted from the open source Clinical Classifications Software (CCS). MethodsWe adapted the CCS crosswalk to 3-digit ICD-9-CM codes for chronic conditions and resolved the one-to-many mappings in ICD-9-CM codes. Using this adapted CCS crosswalk as the reference and referring to existing crosswalks between ICD versions, we extended the mapping to ICDA-8 and ICD-10-CA. Each mapping step was conducted independently by two reviewers and discrepancies were resolved by consensus through deliberation and reference to prior research. We report the frequencies, agreement percentages and 95% confidence intervals (CI) from each step. ResultsWe identified 354 3-digit ICD-9-CM codes for chronic conditions. Of those, 77 (22%) codes had one-to-many mappings; 36 (10%) codes were mapped to a single CCS category and 41 (12%) codes were mapped to combined CCS categories. In total, the codes were mapped to 130 adapted CCS categories with an agreement percentage of 92% (95% CI: 86%–98%). Then, 321 3-digit ICDA-8 codes were mapped to CCS categories with an agreement percentage of 92% (95% CI: 89%–95%). Finally, 3583 ICD-10-CA codes were mapped to CCS categories; 111 (3%) had a fair or poor mapping quality; these were reviewed to keep or move to another category (agreement percentage=77% [95% CI: 69%–85%]). ConclusionsWe developed crosswalks for three ICD versions (ICDA-8, ICD-9-CM, and ICD-10-CA) to 130 clinically meaningful categories of chronic health conditions by adapting the CCS classification. These crosswalks will benefit chronic disease studies spanning multiple decades of administrative health data.

IntroductionMajor osteoporotic fractures (MOF) are associated with significant morbidity and healthcare system burden. Objectives and ApproachWe aimed to determine whether sibling fracture history is associated with MOF risk amongst individuals from a population-based cohort using objectively-ascertained measures of fracture history. This retrospective cohort study used administrative databases from the province of Manitoba, Canada, which has a universal healthcare system. The cohort included individuals aged 40 years and older between 1997 and 2015 with linkage to at least one sibling. The exposure was MOF diagnosis occurring at age 40 years or older in a randomly selected sibling. The outcome was incident clinically-diagnosed MOF (hip, wrist, humerus or spine) identified in hospital and physician records using established case definitions. A multivariable Cox proportional hazards regression was used to test the association of sibling fracture history with the risk of MOF in individuals after adjustment for known fracture risk factors. ResultsThe cohort included 217,519 individuals; 92% were linked to full siblings (i.e., same mother/father) and 49% were females. During a median follow-up of 11 years (IQR 5 -15), 7274 (3.3%) incident MOF cases were identified. Sibling MOF history was associated with increased risk of MOF (HR 1.71, 95% CI 1.48–1.97). The risk was elevated in both men (HR 1.63, 95% CI 1.29-2.06) and women (HR 1.78, 95% CI 1.48-2.13) but was higher among sisters (HR 2.08, 95% CI 1.65-2.61) compared to brothers (HR 1.67, 95% CI 1.20-2.32). In a secondary analysis of sibling fracture site, the highest risk was observed with diagnosis of wrist followed by spine fractures (HR 1.86, 95% CI 1.57-2.21 and HR 1.46, 95% CI 1.08-1.98, respectively). ConclusionSibling fracture history is associated with increased MOF risk in individuals and should be considered as a candidate risk factor for improving fracture risk prediction.

Objectives Previous research suggests an intergenerational influence of diabetes on bone health. We examined the association between parental diabetes and major osteoporotic fracture (MOF) risk in offspring. Methods This population-based cohort study used de-identified administrative health data from Manitoba, Canada, which capture population-level records of hospitalizations, physician visits and drug dispensations. The cohort included individuals 40+ years with at least 1 parent identified in the data between 1997 and 2015. The exposure was parental diagnosis of diabetes since 1970; the outcome was offspring incident MOF diagnosis of the hip, forearm, spine or humerus. Both measures were identified from hospital and physician visit records using validated case definitions. Multivariable Cox proportional hazards regression models tested the association of parental diabetes and offspring MOF risk. Results The cohort included 279,085 offspring; 48.5% were females and 86.8% were ≤44 years of age. Both parents were identified for 89.4% of the cohort; 36.7% had a parental diabetes diagnosis. During a median follow up of 12.0 (interquartile range, 6.0 to 18.0) years, 8,762 offspring had a MOF diagnosis. After adjusting for fracture risk factors, parental diabetes diagnosis was not associated with MOF risk, whether diagnosed in fathers (adjusted hazard ratio [aHR], 1.02; 95% confidence interval [CI], 0.97 to 1.08), mothers (aHR, 1.02; 95% CI, 0.97 to 1.07) or both parents (aHR, 1.01; 95% CI, 0.93 to 1.11). The results remained consistent in a stratified analysis by offspring sex, secondary analysis based on MOF site and sensitivity analyses. Conclusions The results indicate parental diabetes is not associated with offspring MOF risk.

Background Changes in microbiota composition as a result of antibiotics use in early life has been proposed as a possible contributor in the aetiology of autism spectrum disorders (ASD). We aimed to examine the association between early life antibiotic exposure and risk of ASD. Methods This was a population-based cohort study which included all live births in Manitoba, Canada, between 1 April 1998 and 31 March 2016. We used administrative health data from the Manitoba Population Research Data Repository. Exposure was defined as having filled one or more antibiotic prescription during the first year of life. The main outcome was ASD diagnosis. Cox proportional hazards regression models were used to estimate the risk of developing ASD in the overall population and in a sibling cohort. Results Of all subjects in the cohort (n = 214 834), 94 024 (43.8%) filled an antibiotic prescription during the first year of life. During follow-up, 2965 children received an ASD diagnosis. Compared with children who did not use antibiotics during the first year of life, those who received antibiotics had a reduced risk of ASD [adjusted hazardz ratio (HR) 0.91, 95% confidence interval (CI) 0.84-0.99). Number of treatment courses and cumulative duration of antibiotic exposure were not associated with ASD. In the sibling-controlled analysis, early life antibiotic exposure was not associated with ASD (adjusted HR 1.03, 95% CI 0.86-1.23). Conclusions Our findings suggested no clinically significant association between early life antibiotics exposure and risk of autism spectrum disorders, and should provide reassurance to concerned prescribers and parents.

Early childhood antibiotic exposure induces changes in gut microbiota reportedly associated with the development of attention-deficit/hyperactivity disorder (ADHD). We conducted a population-based cohort study to examine the association between antibiotic use in the first year of life and ADHD risk. We included children born in Manitoba, Canada, between 1998 and 2017. Exposure was defined as having filled 1 or more antibiotic prescriptions during the first year of life. ADHD diagnosis was identified in hospital abstracts, physician visits, or drug dispensations. Risk of developing ADHD was estimated using Cox proportional hazards regression in a high-dimensional propensity score–matched cohort (n = 69,738) and a sibling cohort (n = 67,671). ADHD risk was not associated with antibiotic exposure in the matched-cohort (hazard ratio = 1.02, 95% confidence interval: 0.97, 1.08) or in the sibling cohort (hazard ratio = 0.96, 95% confidence interval: 0.89, 1.03). In secondary analyses of the matched cohort, ADHD risk increase was observed in those exposed to 4 or more antibiotic courses or a duration longer than 3 weeks. These associations were not observed in the sibling cohort. We concluded that antibiotic exposure in the first year of life does not pose an ADHD risk on a population level.

BackgroundPrenatal antibiotic exposure induces changes in infants' gut microbiota composition and is suggested as a possible contributor in the development of autism spectrum disorders (ASD). In this study, we examined the association between prenatal antibiotic exposure and the risk of ASD.MethodsThis was a population-based cohort study utilizing the Manitoba Population Research Data Repository. The cohort included 214 834 children born in Manitoba, Canada between April 1, 1998 and March 31, 2016. Exposure was defined as having filled one or more antibiotic prescription during pregnancy. The outcome was autism spectrum disorder diagnosis. Multivariable Cox proportional hazards regression was used to estimate the risk of developing ASD in the overall cohort and in a sibling cohort.ResultsOf all subjects, 80 750 (37.6%) were exposed to antibiotics prenatally. During follow-up, 2965 children received an ASD diagnosis. Compared to children who were not exposed to antibiotics prenatally, those who were exposed had a higher risk of ASD: (adjusted HR 1.10 [95% CI 1.01, 1.19]). The association was observed in those exposed to antibiotics in the second or third trimester (HR 1.11 [95% CI 1.01, 1.23] and 1.17 [95% CI 1.06, 1.30], respectively). In the siblings' cohort, ASD risk estimate remained unchanged (adjusted HR 1.08 [95% CI 0.90, 1.30], although it was not statistically significant.ConclusionsPrenatal antibiotic exposure is associated with a small increase in the risk of ASD. Given the potential of residual confounding beyond what it was controlled through our study design and because of possible confounding by indication, such a small risk increase in the population is not expected to be clinically significant.

To assess knowledge regarding adherence and safety of oral contraceptive pills (OCP) in Saudi women.We conducted a cross-sectional prospective study in an outpatient pharmacy at King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia from April to September 2011. Participants were healthy women aged greater than or equal to 18 years with an OCP prescription for contraception. We used a validated questionnaire to assess their knowledge regarding adherence and safety of OCPs.Four hundred and sixty women participated. Most (79%) knew to take an extra pill if they missed one in less than 12 hours, but only 6.5% knew they also had to use extra protection for the next 7 days if it was more than 12 hours. Multiple logistic regression analyses indicated that years of contraceptive use and educational level are predictive factors of better knowledge regarding adherence. Few were aware of the action if they experienced diarrhea for more than 12 hours (10%) or vomiting within 2 hours (13.5%) of taking an OCP. Only 30% knew of the adverse effects of smoking while on OCPs. Weight gain (51%) was the most commonly reported side effect.Most Saudi women taking OCPs have limited knowledge of its correct use regarding missing pills, vomiting and diarrhea, and poor awareness of the effects of smoking while using OCPs.