Marie Linder

Second-order calibration: bilinear least squares regression and a simple alternative

Abstract We consider calibration of second-order, or hyphenated instruments generating bilinear two-way data for each specimen. The bilinear regression model is to be estimated from a number of specimens of known composition. We propose a simple estimator and study how it works on real and simulated data. The estimator, which we call the SVD (singular value decomposition) estimator is usually not much less efficient than bilinear least squares. The advantages of our method over bilinear least squares are that it is faster and more easily computed, its standard errors are explicit (and derived in the paper), and it has a simpler correlation structure.

Birth outcomes in women with inflammatory bowel disease: effects of disease activity and drug exposure.

Background:Ulcerative colitis (UC) and Crohns disease (CD) have been associated with increased risks of adverse birth outcomes. Disease activity and drug exposure may contribute to the association. Methods:A cohort from the Swedish health registers including 470,110 singleton births in Sweden from July 2006 to December 2010; 1833 to women with UC and 1220 to women with CD. Birth outcomes for women with UC and CD were compared with outcomes among those without disease. Diseased women were categorized by drug exposure, need of surgery, and hospital admissions as (1) no disease activity and (2) stable or (3) flaring disease. Logistic regression was used to calculate odds ratios with adjustments (aOR) for maternal age, parity, smoking status, body mass index, and comorbidity. Results:There were increased risks of preterm birth for both UC (aOR, 1.78; 95% confidence interval [CI], 1.49–2.13) and CD (aOR, 1.65; 95% CI, 1.33–2.06). Risks were more pronounced in women with flaring disease during pregnancy. Risks of small for gestational age, low Apgar score, and hypoglycemia were also increased. The risk of stillbirth was elevated in women with CD, particularly among those with flaring disease (aOR, 4.48; 95% CI, 1.67–11.90). Thiopurine exposure increased risks for preterm birth, both in women with stable (aOR, 2.41; 95% CI, 1.05–5.51) and with flaring disease (aOR, 4.90; 95% CI, 2.76–8.69). Conclusions:Women with UC and CD are at increased risk of adverse birth outcomes, such as stillbirth, growth restriction, and preterm birth, particularly when they suffer from flares throughout pregnancy. Thiopurine exposure seems to further increase risks, independently of disease activity.

Subacute cutaneous lupus erythematosus and its association with drugs: a population‐based matched case–control study of 234 patients in Sweden

Background  Numerous case reports about drug‐induced (DI) subacute cutaneous lupus erythematosus (SCLE) have been published. Various drug types with different latencies has been proposed as triggers for this autoimmune skin disease.

Complications from inflammatory bowel disease during pregnancy and delivery.

BACKGROUND & AIMS Little is known about complications from ulcerative colitis (UC) or Crohns disease (CD) during pregnancy and delivery. We assessed complications by using data from a large, population-based cohort. METHODS We analyzed data from 1209 women with UC, 787 women with CD, and 10,773 women without these diseases (the comparison group) by using the Medical Birth, Patient, and Prescribed Drug Registers of all residents in Sweden. All the women included in the analysis gave birth to a single infant between October 2006 and December 2009. We used data on medical treatment, surgery, and hospital admissions to assess disease activity. Risks of pregnancy and delivery complications were determined from adjusted odds ratios (aORs) with 95% confidence intervals (CIs). RESULTS The risk of venous thromboembolism was increased among women with UC (aOR, 3.78; 95% CI, 1.52-9.38), particularly for those with flaring disease. Women with CD had a higher risk of antepartum hemorrhage (aOR, 1.66; 95% CI, 1.12-2.45), with the highest risks among those with no disease activity. Risks of elective cesarean delivery were more than doubled among women with UC (aOR, 2.44; 95% CI, 2.06-2.88) or CD (aOR, 2.31; 95% CI, 1.89-2.83). Women with UC (aOR, 1.39; 95% CI, 1.13-1.70) or CD (aOR, 1.50; 95% CI, 1.17-1.92) had increased risk for emergency cesarean delivery. Women with an inactive UC or flaring CD had the highest risks of cesarean delivery. CONCLUSIONS Women with UC or CD have more complications during pregnancy and delivery than women without these diseases. Disease activity affects mode of delivery, and thrombophilic events present differently in women with UC vs CD.

Pioglitazone use and risk of bladder cancer in patients with type 2 diabetes: retrospective cohort study using datasets from four European countries

Objective To evaluate the association between pioglitazone use and bladder cancer risk in patients with type 2 diabetes. Design Retrospective cohort study using propensity score matched cohorts. Settings Healthcare databases from Finland, the Netherlands, Sweden, and the United Kingdom. Data comprised country specific datasets of linked records on prescriptions, hospitals, general practitioners, cancer, and deaths. Participants Patients with type 2 diabetes who initiated pioglitazone (n=56 337) matched with patients with type 2 diabetes in the same country exposed to diabetes drug treatments other than pioglitazone (n=317 109). Two matched cohorts were created, using a 1:1 fixed ratio (nearest match cohort) and a 1:10 variable ratio (multiple match cohort). Patients were matched on treatment history and propensity scores accounting for several variables associated with pioglitazone initiation. Main outcome measures Hazard ratios and 95% confidence intervals were estimated by Cox’s proportional hazards model with adjustments for relevant confounders. To assess the robustness of the findings, several sensitivity and stratified analyses were performed. Results In the cohort exposed to pioglitazone treatment, 130 bladder cancers occurred over a mean follow-up time of 2.9 years. In the nearest match and multiple match cohorts not exposed to pioglitazone treatment, 153 and 970 bladder cancers were recorded, with a mean follow‑up time of 2.8 and 2.9 years, respectively. With regards to bladder cancer risk, the adjusted hazard ratio for patients ever exposed versus never exposed to pioglitazone was 0.99 (95% confidence interval 0.75 to 1.30) and 1.00 (0.83 to 1.21) in the nearest and multiple match cohorts, respectively. Increasing duration of pioglitazone use and increasing cumulative dose were not associated with risk of bladder cancer (>48 months of pioglitazone use, adjusted hazard ratio 0.86 (0.44 to 1.66); >40 000 mg cumulative dose, 0.65 (0.33 to 1.26) in the nearest match cohort). Conclusions This study shows no evidence of an association between ever use of pioglitzone and risk of bladder cancer compared with never use, which is consistent with results from other recent studies that also included a long follow-up period. Trial registration Registered to the European Union electronic register of post-authorisation studies (EU PAS register no EUPAS3626).

Risks of Malignant and Non-Malignant Tumours in Tall Women Treated with High-Dose Oestrogen during Adolescence

Background/Aim: High-dose oestrogen treatment has been used to reduce growth in tall adolescent girls. The long-term safety with regard to cancer has not been clarified. Our aim was to study if this growth reduction therapy affects cancer risk later in life. Methods: A cohort study of 369 (172 treated, 197 untreated) Swedish women who in 1973-1993 were assessed for tall adolescent stature was designed. Data were collected from university hospital records, patient questionnaires, and the Swedish Cancer Register. Results: Risks are presented as odds ratios (ORs) with 95% confidence intervals comparing treated to untreated subjects. In treated subjects, the overall OR for having a tumour (malignant or non-malignant) was 1.7 (0.8-3.8). The ORs were 2.3 (0.4-12.8) for breast tumours, 0.8 (0.2-2.6) for gynaecological tumours, and 6.1 (1.04-∞) for melanoma. When limiting to malignant tumours, the crude ORs were of similar magnitude. Conclusion: The OR for any melanoma was higher in treated than in untreated women, suggesting an increased risk of melanoma associated with high-dose oestrogen treatment during adolescence. Although the risk estimates were increased for overall tumours, breast tumours, malignant gynaecological tumours, and malignant melanoma, these associations were not statistically significant. Our results need to be verified in a larger cohort.

Hormone therapy and risk of cardiovascular outcomes and mortality in women treated with statins.

ObjectiveThis work aims to study the effects of hormone therapy (HT) on the risk of cardiovascular outcomes and all-cause mortality in women treated with statins. MethodsWe included women aged 40 to 74 years and living in Sweden who filled a first statin prescription between 2006 and 2007. Women were categorized as HT users or as nonusers. Information on dispensed drugs, comorbidity, cardiovascular outcomes, and all-cause mortality was obtained from national health registers. ResultsA total of 40,958 statin users—2,862 (7%) HT users and 38,096 nonusers—were followed for a mean of 4.0 years. In total, 70% of the women used statins as primary prevention. Among HT users, there were five cardiovascular deaths per 10,000 person-years. The corresponding rate among nonusers was 18, which yielded a hazard ratio of 0.38 (95% CI, 0.12-1.19). The all-cause mortality rates were 33 and 87, respectively, and the hazard ratio was 0.53 (95% CI, 0.34-0.81). There were no associations with cardiovascular events. A similar pattern was found for both primary and secondary prevention. ConclusionsHT is associated with a reduced risk of all-cause mortality in women treated with statins. Although confounding factors, such as lifestyle and disease severity, might have influenced the results, HT does not seem to be detrimental to statin-treated women.

Increased susceptibility to infections before the diagnosis of immune thrombocytopenia

Essentials Infections may trigger autoimmune disease and be a complication of an impaired immune system. The cohort, diagnoses and treatments were retrieved from the Swedish Health Registers. Compared to the population, infection risk is increased before primary immune thrombocytopenia. The incidence of cITP (new definition, International ITP Working Group) is 2.30 per 100 000 person‐years.

Pioglitazone and cause-specific risk of mortality in patients with type 2 diabetes: extended analysis from a European multidatabase cohort study

Objectives Describe and compare the risk of cardiovascular and non-cardiovascular mortality in patients whose antidiabetic therapy is modified to include pioglitazone compared with an alternative antidiabetic medication at the same stage of disease progression. Research design and methods This exploratory linked database cohort analysis used pooled health and mortality data from three European countries: Finland, Sweden and the UK. Propensity score together with exact matching was used to match 31 133 patients with type 2 diabetes first prescribed pioglitazone from 2000 to 2011, to 31 133 patients never prescribed pioglitazone. Exact matching variables were treatment stage, history of diabetes, diabetes complications and cardiovascular disease, and year of cohort entry. Mean follow-up time was 2.60 (SD 2.00) and 2.69 (SD 2.31) years in the pioglitazone and non-pioglitazone-exposed groups, respectively. Crude cause-specific mortality rates were ascertained. Association with pioglitazone use was estimated using Cox proportional hazards models adjusted a priori for country, age, sex, the propensity score quintile and time-dependent variables representing use of antidiabetic drugs. Stepwise testing identified no additional confounders to include in adjusted models. Results The crude mortality rate was lower in the pioglitazone-exposed group than the non-exposed group for both cardiovascular and non-cardiovascular mortality. Adjusted HRs comparing pioglitazone to alternative antidiabetic exposure were 0.58 (95% CI 0.52 to 0.63) and 0.63 (95% CI 0.58 to 0.68) for cardiovascular and non-cardiovascular mortality, respectively. A protective effect associated with pioglitazone was also found for all specific cardiovascular causes. Conclusions This analysis suggests that pioglitazone is associated with a decrease in both cardiovascular and non-cardiovascular mortality. Results should be interpreted with caution due to the potential for residual confounding in this exploratory analysis. Further studies, specifically designed to test the association between pioglitazone use and patient-focused outcomes, are suggested. Study registration number European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP; EUPAS3626).

Use of palivizumab is underestimated in the Swedish Prescribed Drug Register - implications for register-based drug studies.

Background Register studies are a valuable tool, when monitoring the safety of drugs. The Swedish Prescribed Drug Register (PDR) was established in 2005 and keeps records of all prescribed drugs dispensed in community pharmacies. Drugs prescribed in-hospital are not registered on an individual level, which may hamper the validity of register-based studies on drugs potentially administered in-hospital. Objective The objective was to assess the ability of the PDR to identify children treated with the monoclonal antibody palivizumab, which is used for prophylaxis against respiratory syncytial virus (RSV) infection in children. Methods Palivizumab exposure as filled prescriptions recorded in the PDR was assessed by indication of treatment (preterm-born children, bronchopulmonary dysplasia, or hemodynamically significant heart disease) and presented as numbers and proportions. For a random sample of children with an indication for treatment and without record of palivizumab exposure in the drug register, numbers and proportions by indication of treatment as noted in medical records were presented. The extent of underreporting in the drug register was estimated by indication for treatment. Results Through the national health registers, 2,317 children were identified as being at risk for severe infection with RSV infection and 75% had no records indicating palivizumab exposure in the PDR. In a random sample of 176 children at high risk for RSV infection and with no records of palivizumab prescription fills in the PDR, 47% had been treated with palivizumab according to medical records. The PDR underestimated palivizumab treatment with 49% in children born preterm, 42% in children with bronchopulmonary dysplasia, and 23% in those with a hemodynamically significant heart disease. Conclusion Our findings underline the need of improving the information in the Swedish national registers concerning drugs administered in-hospital.