Fabian Hoti

Estradiol-based postmenopausal hormone therapy and risk of cardiovascular and all-cause mortality.

Objective:Data on the health benefits and risks of postmenopausal hormone therapy (HT) are derived mainly from the use of conjugated equine estrogens. Estradiol-based regimens may have a different risk-benefit profile. We evaluated the risk of death caused by coronary heart disease (CHD), stroke, or any disease among users of estradiol-based HT regimens in a nationwide study in Finland. Methods:A total of 489,105 women who used HT from 1994 to 2009 (3.3 million HT exposure years), as indicated in the nationwide reimbursement register and the national Cause of Death Register, were followed. A total of 28,734 HT users died during follow-up; among the deaths, 3,843 were caused by CHD and 2,464 were caused by stroke. Mortality risk in HT users with varying duration of exposure (⩽1 y, >1 to 3 y, >3 to 5 y, >5 to 10 y, or >10 y) was compared with that in an age-matched background population. Results:Risk of CHD death was significantly reduced by 18% to 54% in HT users and was positively related to HT exposure time. Risk of stroke death was also reduced by 18% to 39%, but this reduction was not clearly related to HT exposure time. Risk of all-cause mortality was reduced in HT users by 12% to 38%, almost in linear relationship with duration of exposure. All these risk reductions were comparable in women initiating HT before age 60 years and women initiating HT at age 60 years or older. Conclusions:In absolute terms, the risk reductions mean 19 fewer CHD deaths and 7 fewer stroke deaths per 1,000 women using any HT for at least 10 years.

Real-World Effectiveness of Antipsychotic Treatments in a Nationwide Cohort of 29 823 Patients With Schizophrenia

Importance It has remained unclear whether there are clinically meaningful differences between antipsychotic treatments with regard to preventing relapse of schizophrenia, owing to the impossibility of including large unselected patient populations in randomized clinical trials, as well as residual confounding from selection biases in observational studies. Objective To study the comparative real-world effectiveness of antipsychotic treatments for patients with schizophrenia. Design, Setting, and Participants Prospectively gathered nationwide databases were linked to study the risk of rehospitalization and treatment failure from July 1, 2006, to December 31, 2013, among all patients in Sweden with a schizophrenia diagnosis who were 16 to 64 years of age in 2006 (29 823 patients in the total prevalent cohort; 4603 in the incident cohort of newly diagnosed patients). Within-individual analyses were used for primary analyses, in which each individual was used as his or her own control to eliminate selection bias. Traditional Cox proportional hazards multivariate regression was used for secondary analyses. Main Outcomes and Measures Risk of rehospitalization and treatment failure (defined as psychiatric rehospitalization, suicide attempt, discontinuation or switch to other medication, or death). Results There were 29 823 patients (12 822 women and 17 001 men; mean [SD] age, 44.9 [12.0] years). During follow-up, 13 042 of 29 823 patients (43.7%) were rehospitalized, and 20 225 of 28 189 patients (71.7%) experienced treatment failure. The risk of psychiatric rehospitalization was the lowest during monotherapy with once-monthly long-acting injectable paliperidone (hazard ratio [HR], 0.51; 95% CI, 0.41-0.64), long-acting injectable zuclopenthixol (HR, 0.53; 95% CI, 0.48-0.57), clozapine (HR, 0.53; 95% CI, 0.48-0.58), long-acting injectable perphenazine (HR, 0.58; 95% CI, 0.52-0.65), and long-acting injectable olanzapine (HR, 0.58; 95% CI, 0.44-0.77) compared with no use of antipsychotic medication. Oral flupentixol (HR, 0.92; 95% CI, 0.74-1.14), quetiapine (HR, 0.91; 95% CI, 0.83-1.00), and oral perphenazine (HR, 0.86; 95% CI, 0.77-0.97) were associated with the highest risk of rehospitalization. Long-acting injectable antipsychotic medications were associated with substantially lower risk of rehospitalization compared with equivalent oral formulations (HR, 0.78; 95% CI, 0.72-0.84 in the total cohort; HR, 0.68; 95% CI, 0.53-0.86 in the incident cohort). Clozapine (HR, 0.58; 95% CI, 0.53-0.63) and all long-acting injectable antipsychotic medications (HRs 0.65-0.80) were associated with the lowest rates of treatment failure compared with the most widely used medication, oral olanzapine. The results of several sensitivity analyses were consistent with those of the primary analyses. Conclusions and Relevance Clozapine and long-acting injectable antipsychotic medications were the pharmacologic treatments with the highest rates of prevention of relapse in schizophrenia. The risk of rehospitalization is about 20% to 30% lower during long-acting injectable treatments compared with equivalent oral formulations.

Increased Cardiovascular Mortality Risk in Women Discontinuing Postmenopausal Hormone Therapy

CONTEXT Current guidelines recommend annual discontinuation of postmenopausal hormone therapy (HT) to evaluate whether a woman could manage without the treatment. The impact of HT on cardiovascular health has been widely studied, but it is not known how the withdrawal of HT affects cardiovascular risk. OBJECTIVE We evaluated the risk of cardiac or stroke death after the discontinuation of HT. Design, Patients, Interventions, and Main Outcome Measures: Altogether 332 202 Finnish women discontinuing HT between 1994 and 2009 (data from National Reimbursement register) were followed up from the discontinuation date to death due to cardiac cause (n = 3177) or stroke (n = 1952), or to the end of 2009. The deaths, retrieved from the national Cause of Death Register, were compared with the expected number of deaths in the age-standardized background population. In a subanalysis we also compared HT stoppers with HT users. RESULTS Within the first posttreatment year, the risk of cardiac death was significantly elevated (standardized mortality ratio; 95% confidence interval 1.26; 1.16-1.37), whereas follow-up for longer than 1 year was accompanied with a reduction (0.75; 0.72-0.78). The risk of stroke death in the first posttreatment year was increased (1.63; 1.47-1.79), but follow-up for longer than 1 year was accompanied with a reduced risk (0.89; 0.85-0.94). The cardiac (2.30; 2.12-2.50) and stroke (2.52; 2.28-2.77) death risk elevations were even higher when compared with HT users. In women who discontinued HT at age younger than 60 years, but not in women aged 60 years or older, the cardiac mortality risk was elevated (1.94; 1.51-2.48). CONCLUSIONS Increased cardiovascular death risks question the safety of annual HT discontinuation practice to evaluate whether a woman could manage without HT.

Outbreaks of Streptococcus pneumoniae carriage in day care cohorts in Finland – implications for elimination of transmission

BackgroundDay care centre (DCC) attendees play a central role in maintaining the circulation of Streptococcus pneumoniae (pneumococcus) in the population. Exposure within families and within DCCs are the main risk factors for colonisation with pneumococcal serotypes in DCC attendees.MethodsTransmission of serotype specific carriage was analysed with a continuous time event history model, based on longitudinal data from day care attendees and their family members. Rates of acquisition, conditional on exposure, were estimated in a Bayesian framework utilising latent processes of carriage. To ensure a correct level of exposure, non-participating day care attendees and their family members were included in the analysis. Posterior predictive simulations were used to quantify transmission patterns within day care cohorts, to estimate the basic reproduction number for pneumococcal carriage in a population of day care cohorts, and to assess the critical vaccine efficacy against carriage to eliminate pneumococcal transmission.ResultsThe model, validated by posterior predictive sampling, was successful in capturing the strong temporal clustering of pneumococcal serotypes in the day care cohorts. In average 2.7 new outbreaks of pneumococcal carriage initiate in a day care cohort each month. While 39% of outbreaks were of size one, the mean outbreak size was 7.6 individuals and the mean length of an outbreak was 2.8 months. The role of families in creating and maintaining transmission was minimal, as only 10% of acquisitions in day care attendees were from family members. Considering a population of day care cohorts, a child-to-child basic reproduction number was estimated as 1.4 and the critical vaccine efficacy against acquisition of carriage as 0.3.ConclusionPneumococcal transmission occurs in serotype specific outbreaks of carriage, driven by within-day-care transmission and between-serotype competition. An amplifying effect of the day care cohorts enhances the spread of pneumococcal serotypes within the population. The effect of vaccination, in addition to reducing susceptibility to pneumococcal carriage in the vaccinated, induces a herd effect, thus creating a counter-effect to the amplifying effect of the cohort. Consequently, the critical vaccine efficacy against carriage, required for elimination of transmission, is relatively low. Use of pneumococcal conjugate vaccines is expected to induce a notable herd protection against pneumococcal disease.

Efficient Markov Chain Monte Carlo Implementation of Bayesian Analysis of Additive and Dominance Genetic Variances in Noninbred Pedigrees

Accurate and fast computation of quantitative genetic variance parameters is of great importance in both natural and breeding populations. For experimental designs with complex relationship structures it can be important to include both additive and dominance variance components in the statistical model. In this study, we introduce a Bayesian Gibbs sampling approach for estimation of additive and dominance genetic variances in the traditional infinitesimal model. The method can handle general pedigrees without inbreeding. To optimize between computational time and good mixing of the Markov chain Monte Carlo (MCMC) chains, we used a hybrid Gibbs sampler that combines a single site and a blocked Gibbs sampler. The speed of the hybrid sampler and the mixing of the single-site sampler were further improved by the use of pretransformed variables. Two traits (height and trunk diameter) from a previously published diallel progeny test of Scots pine (Pinus sylvestris L.) and two large simulated data sets with different levels of dominance variance were analyzed. We also performed Bayesian model comparison on the basis of the posterior predictive loss approach. Results showed that models with both additive and dominance components had the best fit for both height and diameter and for the simulated data with high dominance. For the simulated data with low dominance, we needed an informative prior to avoid the dominance variance component becoming overestimated. The narrow-sense heritability estimates in the Scots pine data were lower compared to the earlier results, which is not surprising because the level of dominance variance was rather high, especially for diameter. In general, the hybrid sampler was considerably faster than the blocked sampler and displayed better mixing properties than the single-site sampler.

Clustering of serotypes in a longitudinal study of Streptococcus pneumoniae carriage in three day care centres.

BackgroundStreptococcus pneumoniae (pneumococcus) causes a wide range of clinical manifestations that together constitute a major burden of disease worldwide. The main route of pneumococcal transmission is through asymptomatic colonisation of the nasopharynx. Studies of transmission are currently of general interest because of the impact of the new conjugate-polysaccharide vaccines on nasopharyngeal colonisation (carriage). Here we report the first longitudinal study of pneumococcal carriage that records serotype specific exposure to pneumococci simultaneously within the two most important mixing groups, families and day care facilities.MethodsWe followed attendees (N = 59) with their family members (N = 117) and the employees (N = 37) in three Finnish day care centres for 9 months with monthly sampling of nasopharyngeal carriage. Pneumococci were cultured, identified and serotyped by standard methods.ResultsChildren in day care constitute a core group of pneumococcal carriage: of the 36 acquisitions of carriage with documented exposure to homologous pneumococci, the attendee had been exposed in her/his day care centre in 35 cases and in the family in 9 cases. Day care children introduce pneumococci to the family: 66% of acquisitions of a new serotype in a family were associated with simultaneous or previous carriage of the same type in the child attending day care. Consequently, pneumococcal transmission was found to take place as micro-epidemics driven by the day care centres. Each of the three day care centres was dominated by a serotype of its own, accounting for 100% of the isolates of that serotype among all samples from the day care attendees.ConclusionThe transmission of pneumococci is more intense within than across clusters defined by day care facilities. The ensuing micro-epidemic behaviour enhances pneumococcal transmission.

Family-based clusters of cognitive test performance in familial schizophrenia

BackgroundCognitive traits derived from neuropsychological test data are considered to be potential endophenotypes of schizophrenia. Previously, these traits have been found to form a valid basis for clustering samples of schizophrenia patients into homogeneous subgroups. We set out to identify such clusters, but apart from previous studies, we included both schizophrenia patients and family members into the cluster analysis. The aim of the study was to detect family clusters with similar cognitive test performance.MethodsTest scores from 54 randomly selected families comprising at least two siblings with schizophrenia spectrum disorders, and at least two unaffected family members were included in a complete-linkage cluster analysis with interactive data visualization.ResultsA well-performing, an impaired, and an intermediate family cluster emerged from the analysis. While the neuropsychological test scores differed significantly between the clusters, only minor differences were observed in the clinical variables.ConclusionsThe visually aided clustering algorithm was successful in identifying family clusters comprising both schizophrenia patients and their relatives. The present classification method may serve as a basis for selecting phenotypically more homogeneous groups of families in subsequent genetic analyses.

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).

A semiparametric density estimation approach to pattern classification

A new multivariate density estimator suitable for pattern classifier design is proposed. The data are first transformed so that the pattern vector components with the most non-Gaussian structure are separated from the Gaussian components. Nonparametric density estimation is then used to capture the non-Gaussian structure of the data while parametric Gaussian conditional density estimation is applied to the rest of the components. Both simulated and real data sets are used to demonstrate the potential usefulness of the proposed approach.

Advanced backcross-QTL analysis in spring barley (H. vulgare ssp. spontaneum) comparing a REML versus a Bayesian model in multi-environmental field trials

A common difficulty in mapping quantitative trait loci (QTLs) is that QTL effects may show environment specificity and thus differ across environments. Furthermore, quantitative traits are likely to be influenced by multiple QTLs or genes having different effect sizes. There is currently a need for efficient mapping strategies to account for both multiple QTLs and marker-by-environment interactions. Thus, the objective of our study was to develop a Bayesian multi-locus multi-environmental method of QTL analysis. This strategy is compared to (1) Bayesian multi-locus mapping, where each environment is analysed separately, (2) Restricted Maximum Likelihood (REML) single-locus method using a mixed hierarchical model, and (3) REML forward selection applying a mixed hierarchical model. For this study, we used data on multi-environmental field trials of 301 BC2DH lines derived from a cross between the spring barley elite cultivar Scarlett and the wild donor ISR42-8 from Israel. The lines were genotyped by 98 SSR markers and measured for the agronomic traits “ears per m²,” “days until heading,” “plant height,” “thousand grain weight,” and “grain yield”. Additionally, a simulation study was performed to verify the QTL results obtained in the spring barley population. In general, the results of Bayesian QTL mapping are in accordance with REML methods. In this study, Bayesian multi-locus multi-environmental analysis is a valuable method that is particularly suitable if lines are cultivated in multi-environmental field trials.