DeepPheWAS: an R package for phenotype generation and association analysis for phenome-wide association studies.

SUMMARY: DeepPheWAS is an R package for phenome-wide association studies that creates clinically curated composite phenotypes and integrates quantitative phenotypes from primary care data, longitudinal trajectories of quantitative measures, disease progression and drug response phenotypes. Tools are provided for efficient analysis of association with any genetic input, under any genetic model, with optional sex-stratified analysis, and for developing novel phenotypes. AVAILABILITY AND IMPLEMENTATION: The DeepPheWAS R package is freely available under GNU general public licence v3.0 from at https://github.com/Richard-Packer/DeepPheWAS. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Survival after breast cancer in women with type 2 diabetes using antidiabetic medication and statins: a retrospective cohort study.

Background: We assessed survival of breast cancer in women with type 2 diabetes (T2D) treated with metformin, other types of antidiabetic medication (ADM) and statins.Materials and Methods: The study cohort consisted of women with T2D and diagnosed with breast cancer in Finland in 1998─2011. Mortality rates from breast cancer and other causes were analysed by Cox models, and adjusted hazard ratios (HRs) with 95% confidence intervals (Cls) were estimated in relation to the use of different types of medication.Results: The final cohort consisted of 3,533 women. No clear evidence was found for breast cancer mortality being different in metformin users (HR 0.86, 95% Cl 0.63-1.17), but their other-cause mortality appeared to be lower (HR 0.73, 95% Cl 0.55-0.97) in comparison with women using other types of oral ADM. Other-cause mortality was higher among insulin users (HR 1.45, 95% Cl 1.16-1.80) compared with users of other oral ADMs, other than metformin. Prediagnostic statin use was observed to be associated with decreased mortality from both breast cancer (HR 0.76, 95% Cl 0.63-0.92) and other causes (HR 0.75, 95% Cl 0.64-0.87).Conclusions: We did not find any association between ADM use and disease-specific mortality among women with T2D diagnosed with breast cancer. However, interestingly, prediagnostic statin use was observed to predict reduced mortality from breast cancer and other causes. We hypothesise that treating treatment practices of T2D or hypercholesterolaemia of breast cancer patients might affect overall prognosis of women diagnosed with breast cancer and T2D.

Association of antidiabetic medication and statins with breast cancer incidence in women with type 2 diabetes.

PURPOSE: To address the possible association between the use of metformin, other forms of antidiabetic medication (ADM) and statins with the incidence of breast cancer in women with type 2 diabetes (T2D). METHODS: Data were collected from a Finnish nationwide diabetes database (FinDM). The study cohort consisted of women diagnosed with T2D in 1996-2011 in Finland. In full-cohort analysis, Poisson regression was used to estimate hazard ratios (HRs) in relation to use of metformin, insulin, other forms of oral ADM and statins. In nested case-control analysis, up to 20 controls were matched for age and duration of diabetes to each case of breast cancer. Conditional logistic regression was used to estimate HRs in relation to medication use and cumulative use of different forms of ADM, and statins. RESULTS: 2300 women were diagnosed with breast cancer during follow-up. No difference in breast cancer incidence was observed between metformin users [HR 1.02, 95% confidence interval (CI) 0.93-1.11] or statin users (HR 0.97, 95% CI 0.89-1.05) compared with non-users. In nested case-control analysis the results were similar. Use of insulin (HR 1.18, 95% CI 1.03-1.36) was associated with a slightly increased incidence of breast cancer. CONCLUSIONS: No evidence of an association between the use of metformin or statins and the incidence of breast cancer in women with T2D was found. Among insulin users, a slightly higher incidence of breast cancer was observed.

Prognosis of ovarian cancer in women with type 2 diabetes using metformin and other forms of antidiabetic medication or statins: a retrospective cohort study.

BACKGROUND: Ovarian cancer is one of the most lethal cancers and women with type 2 diabetes (T2D) have even poorer survival from it. We assessed the prognosis of ovarian cancer in women with type 2 diabetes treated with metformin, other forms of antidiabetic medication, or statins. METHODS: Study cohort consisted of women with T2D diagnosed with ovarian cancer in Finland 1998-2011. They were identified from a nationwide diabetes database (FinDM), being linked to several national registers. Patients were grouped according to their medication in the three years preceding ovarian cancer diagnosis. The Aalen-Johansen estimator was used to describe cumulative mortality from ovarian cancer and from other causes in different medication groups. Mortality rates were analysed by Cox models, and adjusted hazard ratios (HR) with 95% confidence intervals (95% CIs) were estimated in relation to the use of different forms of medication. Main outcome measures were death from ovarian cancer and death from other causes. RESULTS: During the accrual period 421 newly diagnosed ovarian cancers were identified in the FinDM database. No evidence was found for any differences in mortality from ovarian cancer or other causes between different antidiabetic medication groups. Pre-diagnostic use of statins was observed to be associated with decreased mortality from ovarian cancer compared with no such use (HR 0.72, 95% CI 0.56-0.93). CONCLUSIONS: Our findings are inconclusive as regards the association between metformin and ovarian cancer survival. However, some evidence was found for improved prognosis of ovarian cancer with pre-diagnostic statin use, requiring cautious interpretation, though.

Antidiabetic medication, statins and the risk of endometrioid endometrial cancer in patients with type 2 diabetes.

OBJECTIVE: To gain further evidence of an association between the incidence of endometrial cancer (EC) and the use of metformin, other antidiabetic medication (ADM) and statins in women with type 2 diabetes (T2D). METHODS: A retrospective cohort of 92,366 women with newly diagnosed T2D was obtained from a diabetes register (FinDM). 590 endometrioid ECs were observed during the follow-up time. Poisson regression was utilized to estimate the hazard ratios (HRs) with 95% confidence intervals (95% CIs) of the endometrioid EC in relation to the use of metformin, other oral ADM, insulin and statins. Nested case-control analyses were performed, where up to 20 controls were matched for age and duration of DM for each EC case. The HRs were estimated by conditional logistic regression for never/ever and cumulative use of different forms of ADM and statins. RESULTS: In the case-control analyses the use of metformin (HR 1.24, 95% CI 1.02-1.51) and other oral ADM (HR 1.25, 95% CI 1.04-1.50) was associated with an increased incidence of endometrioid EC compared to no ADM use. No difference was observed between metformin users and those using other oral ADMs. The use of statins was inversely related to the incidence of endometrioid EC (HR 0.78, 95% CI 0.65-0.94). Results from the full cohort analysis supported this finding. CONCLUSIONS: In our study the use of metformin or other oral forms of ADM was not associated with a lowered risk of endometrioid EC in women with T2D. Instead statins were observed to be inversely associated with endometrioid EC in this population.

Association of antidiabetic medication and statins with survival from ductal and lobular breast carcinoma in women with type 2 diabetes.

We investigated the survival of female patients with pre-existing type 2 diabetes (T2D) diagnosed with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) of breast, in relation to the use of metformin, other antidiabetic medication (ADM) and statins. The study cohort consisted of 3,165 women (2,604 with IDC and 561 with ILC). The cumulative mortality from breast cancer (BC) and from other causes was calculated using the Aalen-Johansen estimator. The cause-specific mortality rates were analysed by Cox models, and adjusted hazard ratios (HRs) were estimated for the use of different medications. No evidence of an association of metformin use with BC mortality was observed in either IDC (HR 0.92, 95% confidence interval [CI] 0.64-1.31) or ILC (HR 0.68, 95% CI 0.32-1.46) patients, when compared to other oral ADMs. The mortality from other causes was found to be lower amongst the IDC patients using metformin (HR 0.64, 95% CI 0.45-0.89), but amongst ILC patients the evidence was inconclusive (HR 1.22, 95% CI 0.64-2.32). Statin use was consistently associated with reduced mortality from BC in IDC patients (HR 0.77, 95% CI 0.62-0.96) and ILC patients (HR 0.59, 95% CI 0.37-0.96), and also mortality from other causes in IDC patients (HR 0.81, 95% CI 0.67-0.96) and in ILC patients (HR 0.66, 95% CI 0.43-1.01). We found no sufficient evidence for the possible effects of metformin and statins on the prognosis of BC being different in the two histological subtypes.

Association of Metformin, Other Antidiabetic Medications, and Statins With Incidence of Colon Cancer in Patients With Type 2 Diabetes.

BACKGROUND: Metformin and statins may have anticancer effects, with plausible cellular mechanisms. However, the association of these agents with the risk of colorectal cancer is unclear. PATIENTS AND METHODS: This was a retrospective cohort study on a large population (N = 316,317) of patients with type 2 diabetes. Data were obtained from the Diabetes in Finland database (FinDM). In a full cohort analysis, hazard ratios (HRs) with their 95% confidence intervals (CIs) for ever use versus never use were estimated using a multiple Poisson regression model. A nested case-control design within the cohort was used to examine the association of colon cancer (CC) with the defined daily dose of medication. The data were analyzed by conditional logistic regression. The analyses were adjusted for the patient's age, sex, and duration of diabetes. RESULTS: In total, 1351 CC cases were diagnosed during 1996-2011. The results revealed insufficient evidence for an association between metformin (HR, 1.01; 95% CI, 0.90-1.14), other oral antidiabetic medications (HR, 1.05; 95% CI, 0.93-1.19), insulin (HR, 1.02; 95% CI, 0.86-1.22), or statins (HR, 0.94; 95% CI, 0.84-1.05) and the incidence of CC in the full cohort analysis. The results from the case-control study were similar, with no consistent trend in the incidence of CC according to the cumulative dose of metformin or the other studied medications. CONCLUSION: This study found insufficient evidence for an association between metformin, insulin, other oral type 2 diabetes medications, or statins and the incidence of CC.

Out-of-home placement in early childhood and psychiatric diagnoses and criminal convictions in young adulthood: a population-based propensity score-matched study.

BACKGROUND: To ensure their protection and healthy development, children exposed to adverse family circumstances might be placed in foster homes, institutions, or kinship care (out-of-home placement). We aimed to compare the rates of psychiatric diagnoses and criminal convictions in young adulthood (ages 18-25 years) among children who were first placed at ages 2-6 years with those of children who were not placed and who had similar sociodemographic and family characteristics. METHOD: We did a population-wide cohort study using the 1987 Finnish Birth Cohort, which collects longitudinal data linking nationwide child welfare, medical, and criminal registers for all 59 476 livebirths in Finland in 1987. The exposure was the first out-of-home placement at ages 2-6 years. Outcomes were rates of psychiatric diagnoses, criminal convictions, and prescriptions for psychotropic medication filled at ages 18-25 years. We matched cases to non-placed controls using propensity score matching on parental characteristics (eg, age, psychiatric diagnoses, education, family structure) and child characteristics (eg, neurodevelopmental problems, prematurity). Differences in adult outcomes between children placed and matched controls were assessed by use of logistic regression on the matched cohort. FINDINGS: Of 54 814 individuals with complete data, 388 (1%) were first placed at ages 2-6 years; matched controls were identified for 386 of these children. At ages 18-25 years, those who had been placed as children had greater odds than never-placed controls of substance-related disorders (odds ratio 2·10, 95% CI 1·27-3·48), psychotic or bipolar disorders (3·98, 1·80-8·80), depression or anxiety (2·15, 1·46-3·18), neurodevelopmental disorders (3·59, 1·17-11·02), or other disorders (2·06, 1·25-3·39). Participants who were placed had more psychotropic medication prescriptions (1·96, 1·38-2·80) and higher rates of criminal convictions (violent offences, 2·43, 1·61-3·68; property offences, 1·86, 1·17-2·97). INTERPRETATION: Preschool children who are placed out-of-home are at risk of adverse outcomes as adults, even accounting for their initial circumstances. It is important to explore which conditions lead to more or less favourable outcomes in child protection. FUNDING: Academy of Finland.

Temporal changes in the incidence of treated psychiatric and neurodevelopmental disorders during adolescence: an analysis of two national Finnish birth cohorts.

BACKGROUND: Comprehensive overviews of the temporal changes in treated psychiatric and neurodevelopmental disorders during adolescence are scarce. We reviewed data from two national cohorts, 10 years apart, to establish the change in use of specialised services for psychiatric and neurodevelopmental diagnoses in Finland. METHODS: We compared the nationwide register-based incidence of psychiatric and neurodevelopmental diagnoses between the 12th birthday and 18th birthday of adolescents born in Finland in 1987 and 1997. Adolescents who emigrated or died before their 12th birthday and those with missing covariate data were excluded, as were those who, when aged 11 years, had lived in a municipality belonging to a hospital district with obviously incomplete data reports during any follow-up years in our study. Our primary outcomes were time to incident specialised service use for any psychiatric or neurodevelopmental disorder and for 17 specific diagnostic classes. We also investigated whether adolescents who died by suicide had accessed specialised services before their deaths. FINDINGS: The cumulative incidence of psychiatric or neurodevelopmental disorders increased from 9·8 in the 1987 cohort to 14·9 in the 1997 cohort (difference 5·2 percentage points [95% CI 4·8-5·5]) among girls, and from 6·2 in the 1987 cohort to 8·8 in the 1997 (2·6 percentage points [2·4-2·9]) among boys. The hazard ratio for the overall relative increase in neurodevelopment and psychiatric disorders in the 1997 cohort compared with the 1987 cohort was 1·6 (95% CI 1·5-1·8) among girls and 1·5 (1·4-1·6) among boys. Of the studied diagnostic classes, we noted significant (ie, p<0·001) relative increases for ten of 17 diagnoses among girls and 11 among boys. Of the adolescents who died by suicide before age 18, only five of 16 in the 1987 cohort and two of 12 in the 1997 cohort had used specialised services in the 6 months before their death. INTERPRETATION: The large absolute rise in service use for psychiatric or neurodevelopmental disorders points to the need to deliver effective treatment to a rapidly increased patient population, whereas the relative increase in specific diagnoses should inform clinical practice. Despite increasing service use, identification of adolescents at risk of suicide remains a major public health priority. FUNDING: Academy of Finland, Brain and Behavior Research Foundation, Finnish Medical Foundation.

Antidiabetic Medication, Statins and the Risk and Prognosis of Non-endometrioid Endometrial Cancer in Women with Type 2 Diabetes.

AIM: To determine the incidence and prognosis of non-endometrioid endometrial cancer (EC) in relation to the use of metformin, other antidiabetic medication (ADM) and statins in patients with type 2 diabetes (T2D). MATERIALS AND METHODS: In order to analyze the incidence and prognosis of non-endometrioid EC, two cohorts were obtained from a nationwide diabetes database (FinDM); 57 non-endometrioid ECs were observed in a cohort of 92,366 women with newly-diagnosed T2D during the follow-up (1996 to 2011) to assess the incidence, and a retrospective cohort of 105 women with T2D diagnosed with non-endometrioid EC (1998 to 2011) was used to estimate cumulative mortality from EC and other causes of death. Hazard ratios (HRs) with 95% confidence intervals (CIs) for EC incidence were estimated in the full-cohort analysis and in the nested case-control analysis, matched for age and duration of T2D. Cumulative mortality was estimated by using the Aalen-Johansen estimator. Cause-specific mortality rates were analyzed by using Cox models regarding the pre-diagnostic use of different forms of ADM and statins. RESULTS: In the nested case-control analysis, the use of metformin was not associated with the risk of non-endometrioid EC (HR=1.09, 95% CI=0.59-2.00), whereas statin use was associated with a lower risk (HR=0.47, 95% CI=0.26-0.84). The results from the full-cohort analysis supported these findings. Mortality from non-endometrioid EC was not different between users of metformin and other types of oral ADM (HR=1.56, 95% CI=0.40-6.07) but was observed to be lower in statin users (HR=0.41, 95% CI=0.20-0.82). CONCLUSION: Our findings were inconclusive regarding the association of metformin with the risk and prognosis of non-endometrioid EC. However, statin use was associated with a lower incidence and mortality from this disease.