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Purpose: Large health-care databases are increasingly used for research on drug utilization and safety in pregnancy. For the German Pharmacoepidemiological Research Database (GePaRD), covering ~20% of the German population, algorithms have been developed to identify pregnancies, to estimate their date of onset and to link mothers to their babies. Using this methodology, we aimed to conduct a proof-of-concept analysis on the known association between valproate (VPA) exposure in early pregnancy and spina bifida in the exposed child., Methods: We identified all pregnancies in GePaRD between 2006 and 2016 in women aged 12 to 50 years. To each VPA dispensation of these women, an exposure period was assigned, based on the dispensation date and the number of defined daily doses in the dispensed package. A pregnancy was classified as exposed to VPA in the critical time window if this exposure period overlapped with the first 55 days of pregnancy. Risk ratios were calculated for spina bifida in live births and induced abortions comparing VPA-exposed ones to all pregnancies., Results: Overall, we identified 1 271 384 pregnancies fulfilling the inclusion criteria. Of these, 668 pregnancies (0.053%) were classified as exposed to VPA in the critical time window regarding spina bifida. An induced abortion accompanied by a diagnosis of spina bifida was observed in one of the VPA-exposed pregnancies (0.15%) and in 154 of all pregnancies (0.012%), yielding a risk ratio of 12.4 (95% confidence interval [CI]: 1.7-88.2). Out of 775 875 pregnancies ending in a live birth, 366 (0.047%) were classified as VPA exposed. A diagnosis of spina bifida was coded in 3 of 366 VPA-exposed live births (0.82%) and in 260 of all live births (0.03%), yielding a relative risk of 24.5 (95% CI: 7.9-76.0)., Conclusions: Our proof-of-concept analysis based on GePaRD showed a strong association between intrauterine exposure to VPA and occurrence of spina bifida. The results are plausible and consistent with the literature, supporting the suitability of GePaRD and the developed algorithms to conduct studies on drug safety in pregnancy., (© 2022 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Background: Breast cancer (BC) survivors often suffer from late and long-term residual symptoms of the disease and its treatment. To date, long-term health-related quality of life (HRQoL) in breast cancer survivors has been seldom investigated and rarely compared to unaffected women (controls). Aim: This study aimed to investigate HRQoL over time using patient-reported status before diagnosis, during treatment, 1 year post-surgery, approx. 5 years and ≥10 years post-diagnosis. We also compared survivors' HRQoL with controls' still alive 10 years after recruitment. Methods: Data from the German population-based Mamma Carcinoma Risk Factor Investigation (MARIE) cohort of 1123 BC patients aged 50-74 years at diagnosis (2002-2005) and of 3453 matched controls were used for analysis. HRQoL was assessed with the European Organization for Research and Treatment of Cancer (EORTC QLQ-C30) questionnaire. All analyses were conducted for all ages as well as stratified according to three age groups (≤58 years, 59-64 years, ≥64 years). Differences in survivors' general HRQoL before, during, and after therapy were investigated using a t-test/Wilcoxon signed-rank test. Changes in the HRQoL of survivors stratified by age from FU1 to FU2 were assessed via repeated analysis of variance. The HRQoL of survivors compared to the controls at FU2 was analyzed using an analysis of variance. Results: Over all ages, the general HRQoL in patients improved in the first 5 years post-diagnosis. In the subsequent years, HRQoL slightly deteriorated but was comparable to that of the controls. Younger survivors mostly improved their HRQoL from the 5 to 10-year follow-up but remained negatively affected for most functioning and symptom scales compared to controls. In older survivors, HRQoL hardly changed over time and detriments were less pronounced compared to controls, except for insomnia. Conclusions: Restrictions of HRQoL persist for more than 10 years and are most prominent among younger survivors. Researchers and clinicians should be aware of such potential deteriorations and age-dependent differences in order to optimize/adapt long-term cancer survivor care.

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer., (© 2020 The Authors. Genetic Epidemiology published by Wiley Periodicals, Inc.)

Recent studies have shown that moving in synchrony with auditory stimuli boosts attention allocation and verbal learning. Furthermore rhythmic tones are processed more efficiently than temporally random tones ('timing effect'), and this effect is increased when participants actively synchronize their motor performance with the rhythm of the tones, resulting in auditory-motor synchronization. Here, we investigated whether this applies also to sequences of linguistic stimuli (syllables). We compared temporally irregular syllable sequences with two temporally regular conditions where either the interval between syllable onsets (stimulus onset asynchrony, SOA) or the interval between the syllables' vowel onsets was kept constant. Entrainment to the stimulus presentation frequency (1 Hz) and event-related potentials were assessed in 24 adults who were instructed to detect pre-defined deviant syllables while they either pedaled or sat still on a stationary exercise bike. We found larger 1 Hz entrainment and P300 amplitudes for the SOA presentation during motor activity. Furthermore, the magnitude of the P300 component correlated with the motor variability in the SOA condition and 1 Hz entrainment, while in turn 1 Hz entrainment correlated with auditory-motor synchronization performance. These findings demonstrate that acute auditory-motor coupling facilitates phonetic encoding., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.

Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry., Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP)., Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10 -8 . For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10 -7 , hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10 -7 , HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster., Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Higher lignan exposure has been associated with lower all-cause mortality (ACM) and breast cancer-specific mortality (BCSM) for postmenopausal breast cancer patients. However, the biological mechanisms underpinning these associations are still unclear. We investigated for the first time whether and to what extent the association between enterolactone (ENL), the major lignan metabolite, and postmenopausal breast cancer prognosis is mediated by inflammatory biomarkers. Circulating concentrations of ENL and inflammatory markers were measured in a population-based prospective cohort of 1,743 breast cancer patients recruited between 2002 and 2005 and followed-up until 2009. Hazard ratios (HR) and 95% CIs were estimated using multivariable Cox regression. Mediation analysis was performed to estimate the percentage association between ENL (log2) and ACM, BCSM and distant disease-free survival (DDFS), which is mediated by C-reactive protein (CRP) (log2), as the strongest potential mediator, and also interleukin (IL)-10. Median serum/plasma ENL and CRP concentrations for all patients, including 180 deceased patients, were 23.2 and 17.5 nmol/L, and 3.2 and 6.5 mg/l, respectively. ENL concentrations were significantly inversely associated with ACM, BCSM and DDFS (per doubling of ENL concentrations: HRs 0.93 [0.87, 0.99], 0.91 [0.84, 0.99] and 0.92 [0.87, 0.99]), after adjusting for prognostic factors and BMI. Estimated 18, 14 and 12% of the effects of ENL on ACM, BCSM and DDFS, respectively, were mediated through CRP. No mediational effect of IL-10 was found. We provide first evidence that the proinflammatory marker CRP may partially mediate the association of ENL with postmenopausal breast cancer survival, which supports hormone-independent mechanisms., (© 2018 UICC.)

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10 -6 , including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.

Purpose: Recent cohort studies demonstrated better overall survival (OS) or breast cancer-specific survival (BCS) for breast-conserving therapy (BCT) followed by radiation (RT) compared to mastectomy alone (MT). This is the first observational study in which adjustments for a comprehensive set of prognostic factors, adjuvant therapies, mode of detection, and comorbidities were possible to investigate OS, BCS, as well as recurrence risk of patients undergoing BCT + RT, MT + RT, or MT., Methods: Women aged 50-74 years at diagnosis of early-stage invasive breast cancer (I-IIIa) between 2001 and 2005 at the German population-based case-control study (MARIE study) were recruited and followed prospectively as a case cohort until 2015. Kaplan-Meier estimates and stepwise adjusted multivariable Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI)., Results: The 2762 patients included were followed up for a median of 11.9 years (95% CI 11.8-12.0). 74.2% of patients underwent BCT + RT; 10.3% MT + RT and 15.6% MT alone. Compared to patients treated with MT alone, patients treated with BCT + RT showed non-statistically significant improved OS (HR 0.79, 95% CI 0.61-1.02), BCS (HR 0.79, 95% CI 0.55-1.12), and no difference in recurrence risks (HR 1.01, 95% CI 0.74-1.37). For patients treated with MT + RT, there were no differences in OS (HR 1.06, 95% CI 0.75-1.50), BCS (HR 1.17, 95% CI 0.75-1.82), or recurrence risk (HR 1.33, 95% CI 0.89-1.97)., Conclusions: Among patients with early-stage breast cancer, clinical outcomes more than 10 years after diagnosis did not differ between the primary treatment options BCT + RT, MT + RT versus MT alone after full adjustment.

Background: Studies of cohorts of breast cancer (BC) patients diagnosed before 1990 showed radiotherapy (RT) to be associated with increased cardiovascular (CVD) and lung cancer mortality many years after diagnosis. In the late 1990s, improvements in RT planning techniques reduced radiation doses to normal tissues. Recent studies did not consistently report higher RT-related mortality for CVD and second cancers. Aim of the study was to analyze specific causes of death after 3D-conformal RT in a recent BC cohort., Methods: Stage I-III BC patients diagnosed 2001-2005 and enrolled in the population based MARIEplus study were followed-up for 11.9 years (median). Associations between adjuvant RT and cause-specific mortality were analyzed by using competing risks models, yielding subdistribution hazard ratios (SHR) for RT directly related to cumulative incidences. Models were adjusted for differences in baseline characteristics applying inverse-probability-of-treatment-weighting (IPTW)., Results: Of the 2951 patients, 2439 (83.0%) received RT. No significant association of RT with lung cancer mortality (SHR IPTW 0.88, 0.35-2.12), other cancer mortality (SHR IPTW 1.04, 95% CI 0.62-1.73) or cardiac mortality was observed (SHR IPTW 1.57, 0.75-3.29). Mortality from lung and other diseases were significantly lower in irradiated women (SHR IPTW 0.39, 95% CI 0.17-0.90 and SHR IPTW 0.58, 95% CI 0.34-0.97, respectively)., Conclusion: In line with recent studies, 3D-conformal RT did not significantly increase mortality from non-BC causes in the German MARIEplus cohort. Since long-term data are still sparse and event rates low in BC-cohorts, who received modern RT, investigation of possible late RT effects on mortality beyond 14 years of follow-up is warranted., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10 -8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10 -8 . The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

Scope: Phytoestrogens (PE) may improve breast cancer prognosis by modifying tumor prognostic markers, such as cell proliferation marker Ki-67 and human epidermal growth factor receptor 2 (HER2). Epidemiological evidence linking lignans and isoflavones to Ki-67 and HER2 is limited. We examined associations between the major metabolites of lignans and isoflavones - enterolactone (ENL) and genistein (GEN) - respectively, and Ki-67 expression and HER2 in tumor tissue of breast cancer patients., Methods and Results: Data from 1060 invasive breast cancer patients from the population-based MARIE study were used. Multivariate-adjusted linear (Ki-67 log-transformed) and quantile regression, and logistic regression analyses (HER2, Ki-67 dichotomized) were performed to calculate β estimates and ORs, respectively. Median post-diagnostic ENL and GEN concentrations were 19.5 and 4.8 nmol/L, respectively. Median Ki-67 was 12.0%, and 21.2% of the tumors were HER2+. After adjustment, there was an inverse association between GEN and Ki-67 at high expression levels (OR for Ki-67 ≥20% versus <20% of 0.93 (95%CI [0.87;0.99]) per 10 nmol/L GEN increment)., Conclusion: Our findings indicate an inverse association between GEN and Ki-67 at high levels of Ki-67 expression. Additional investigations are recommended to confirm our findings and to further elucidate mechanisms linking PE metabolites to breast cancer survival., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Introduction: Use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with an increased relative risk of acute myocardial infarction (AMI), but the label warnings refer particularly to patients with cardiovascular risk factors. The magnitude of relative AMI risk for patients with and without cardiovascular risk factors varies between studies depending on the drugs and doses studied., Objectives: The aim of our study was to estimate population-based relative AMI risks for individual and widely used NSAIDs, for a cumulative amount of NSAID use, and for patients with and without a prior history of cardiovascular risk factors., Methods: Based on data from the German Pharmacoepidemiological Research Database (GePaRD) of about 17 million insurance members from four statutory health insurance providers, for the years 2004-2009, a nested case-control study was conducted within a cohort of 3,476,931 new NSAID users classified into current, recent, or past users. Up to 100 controls were matched to each case by age, sex, and length of follow-up using risk set sampling. Multivariable conditional logistic regression was applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Duration of NSAID use was calculated by the cumulative amount of dispensed defined daily doses (DDDs), and stratified analyses were conducted for potential effect modifiers., Results: Overall, 17,236 AMI cases were matched to 1,714,006 controls. Elevated relative AMI risks were seen for current users of fixed combinations of diclofenac with misoprostol (OR 1.76, 95% CI 1.26-2.45), indometacin (1.69, 1.22-2.35), ibuprofen (1.54, 1.43-1.65), etoricoxib (1.52, 1.24-1.87), and diclofenac (1.43, 1.34-1.52) compared with past use. A low cumulative NSAID amount was associated with a higher relative AMI risk for ibuprofen, diclofenac, and indometacin. The relative risk associated with current use of diclofenac, fixed combinations of diclofenac with misoprostol, etoricoxib, and ibuprofen was highest in the younger age group (<60 years) and similar for patients with or without major cardiovascular risk factors., Conclusion: Relative AMI risk estimates differed among the 15 investigated individual NSAIDs. Diclofenac and ibuprofen, the most frequently used NSAIDs, were associated with a 40-50% increased relative risk of AMI, even for low cumulative NSAID amounts. The relative AMI risk in patients with and without cardiovascular risk factors was similarly elevated.

Background: Shortly after the human papillomavirus (HPV) vaccine recommendation and hence the reimbursement of vaccination costs for the respective age groups in Germany in 2007, changes in the incidence of anogenital warts (AGWs) were observed, but it was not clear at what level the incidence would stabilize and to what extent herd immunity would be present. Given the relatively low HPV vaccination coverage in Germany, we aimed to assess potential vaccination herd immunity effects in the German setting., Methods: A retrospective open cohort study with data from more than nine million statutory health insurance members from 2005 to 2010 was conducted. AGW cases were identified using ICD-10-codes. The incidence of AGWs was estimated by age, sex, and calendar quarter. Age and sex specific incidence rate ratios were estimated comparing the years 2009-2010 (post-vaccination period) with 2005-2007 (pre-vaccination period)., Results: Incidence rate ratio of AGWs for the post-vaccination period compared to the pre-vaccination period showed a u-shaped decrease among the 14- to 24-year-old females and males which corresponds well with the reported HPV vaccination uptake in 2008. A maximum reduction of up to 60% was observed for the 16- to 20-year-old females and slightly less pronounced (up to 50%) for the 16- and 18-year-old males. Age groups outside of the range 14-24 years demonstrated no decrease. The decrease of incidence occurred in both sexes early after the vaccine recommendation and stabilized at lower levels in 2009-2010., Conclusions: A relative reduction of up to 50% among males of approximately similar age groups as that of females receiving the HPV vaccination suggests herd protection resulting from assortative mixing by age. The early decrease among males can be reduced over time due to partner change.

Background: Herpes zoster (HZ) is caused by reactivation of the latent varicella-zoster virus (VZV). A severe complication of HZ is VZV vasculopathy which can result in ischemic or hemorrhagic stroke. The aims of our study were to assess the risk of stroke after the onset of HZ and to investigate the roles of stroke subtype, HZ location and the time interval between HZ onset and stroke., Methods: A self-controlled case-series study was performed on a cohort of patients with incident stroke recorded in the German Pharmacoepidemiological Research Database (GePaRD), which covers about 20 million persons throughout Germany. We estimated adjusted incidence rate ratios (IRR) by comparing the rate of stroke in risk periods (i.e., periods following HZ) with the rate of stroke in control periods (i.e., periods without HZ) in the same individuals, controlling for both time-invariant and major potentially time-variant confounders., Results: The cohort included 124,462 stroke patients, of whom 6,035 (5%) had at least one HZ diagnosis identified in GePaRD either as main hospital discharge diagnosis or as HZ treated with antivirals. The risk of stroke was about 1.3 times higher in the risk periods 3 months after HZ onset, than in the control periods (IRR: 1.29; 95% confidence interval: 1.16-1.44). An elevated risk of similar magnitude was observed for ischemic and unspecified stroke, but a 1.5-fold higher risk was observed for hemorrhagic stroke. A slightly stronger effect on the risk of stroke was also observed during the 3 months after HZ ophthalmicus (HZO) onset (1.59; 1.10-2.32). The risk was highest 3 and 4 weeks after HZ onset and decreased thereafter., Conclusions: Our study corroborates an increased risk of stroke after HZ, which is highest 3 to 4 weeks after HZ onset. The results suggest that the risk is more pronounced after HZO and is numerically higher for hemorrhagic than for ischemic stroke., Competing Interests: HB is a full time employee of Sanofi Pasteur MSD. This study was funded by Sanofi Pasteur. TS, SB, KT, and EG as employees of the Leibniz Institute for Prevention Research and Epidemiology – BIPS have performed research studies paid by pharmaceutical companies (Bayer-Schering, Celgene, GSK, Mundipharma, Novartis, Purdue, Sanofi-Aventis, Sanofi- Pasteur, Stada, and Takeda) unrelated to this study. EG has been a consultant to Bayer, Novartis, Nycomed, Takeda, GSK, Astellas on topics unrelated to the subject of this study. SB left BIPS and joined Novartis Pharma AG after conduct of the study. Except for finalization of the manuscript, the entire analysis and results interpretation was performed under BIPS affiliation. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.