Biostatistics and Research Decision science

Oss, Netherlands

Biostatistics and Research Decision science

Oss, Netherlands
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Elferink M.G.L.,University of Groningen | Olinga P.,University of Groningen | van Leeuwen E.M.,Molecular Design and Informatics | Bauerschmidt S.,Molecular Design and Informatics | And 5 more authors.
Toxicology and Applied Pharmacology | Year: 2011

In the process of drug development it is of high importance to test the safety of new drugs with predictive value for human toxicity. A promising approach of toxicity testing is based on shifts in gene expression profiling of the liver. Toxicity screening based on animal liver cells cannot be directly extrapolated to humans due to species differences. The aim of this study was to evaluate precision-cut human liver slices as in vitro method for the prediction of human specific toxicity by toxicogenomics. The liver slices contain all cell types of the liver in their natural architecture. This is important since drug-induced toxicity often is a multi-cellular process. Previously we showed that toxicogenomic analysis of rat liver slices is highly predictive for rat in vivo toxicity. In this study we investigated the levels of gene expression during incubation up to 24. h with Affymetrix microarray technology. The analysis was focused on a broad spectrum of genes related to stress and toxicity, and on genes encoding for phase-I, -II and -III metabolizing enzymes and transporters. Observed changes in gene expression were associated with cytoskeleton remodeling, extracellular matrix and cell adhesion, but for the ADME-Tox related genes only minor changes were observed. PCA analysis showed that changes in gene expression were not associated with age, sex or source of the human livers. Slices treated with acetaminophen showed patterns of gene expression related to its toxicity. These results indicate that precision-cut human liver slices are relatively stable during 24. h of incubation and represent a valuable model for human in vitro hepatotoxicity testing despite the human inter-individual variability. © 2011 Elsevier Inc.


Bitzer J.,University of Basel | Cupanik V.,R.Ø.S.A. | Fait T.,Charles University | Gemzell-Danielsson K.,Karolinska University Hospital | And 4 more authors.
European Journal of Contraception and Reproductive Health Care | Year: 2013

Objectives To investigate which characteristics of women and healthcare professionals (HCPs) were associated with changing to another combined hormonal contraceptive (CHC) method after contraceptive counselling. Methods CHOICE was a cross-sectional survey in which 18,787 women were counselled about combined hormonal contraceptives, during which their contraceptive methods preferred both prior to and after counselling were recorded. In this subanalysis, characteristics associated with changing the method after counselling were determined using logistic regression models. Results The probability of intending to change from the pill to another method was associated with being older; university-educated; being in a steady relationship; a prior unintended pregnancy; a younger HCP or one who recommended methods other than the pill. Changing to the patch was associated with a female HCP or a HCP who recommended the patch or an injectable. Changing to the ring was associated with being over 21 years; university-educated; being in a relationship; previous hormonal method use; and counselling by a female HCP, a HCP < 60 years old, or a HCP who recommended the ring or an implant. The country of residence influenced these changes in a complex pattern. Conclusions Women's choice of CHC methods after contraceptive counselling are influenced by their age, educational background, relationship status, prior unplanned pregnancies and country of residence, as well as age, gender and preferences of their HCP. © 2013 The European Society of Contraception and Reproductive Health.


Gemzell-Danielsson K.,Karolinska University Hospital | Thunell L.,Skåne University Hospital | Lindeberg M.,Medical Affairs | Tyden T.,Uppsala University | And 2 more authors.
Acta Obstetricia et Gynecologica Scandinavica | Year: 2011

Objective. To study the influence of counseling on women's contraceptive decisions. Design. A cross-sectional multicenter study. Setting. Seventy Swedish family planning clinics. Population. Women aged 15-40 years attending for a contraceptive consultation who expressed interest in a combined hormonal contraceptive (CHC) method. Methods. Structured counseling about three CHCs and questionnaires completed after counseling from the healthcare professional. Main Outcome Measures. Method originally requested, perceptions of CHC attributes, method chosen and reasons for the choice. Results. In all, 173 healthcare professionals and 1 944 women participated. The mean standard deviation (SD) age of the women was 22.6(6.1) years. After structured counseling, a majority of women (56.0%; n=1 069; 95% confidence interval (CI) 53.1-58.9) chose the daily pill, 6.2% (n=118; 95% CI 4.9-7.8) chose the weekly patch, and 22.5% (n=430; 95% CI 20.2-25.1) chose the monthly ring. The weekly patch was chosen more often after counseling (6.2 vs 2.4% before counseling; p<0.0001). The greatest change was in the proportion of women who chose the contraceptive ring after counseling (22.5% vs. 8.5% before counseling; p<0.0001). The proportion of undecided women after counseling was reduced considerably (3.9% vs. 27.8% before counseling). Among the 523 women who were undecided before counseling, 50.6% chose the pill, 10.2% the patch and 24.6% the ring, while 20.9% of women who initially requested the pill changed to another method. Conclusions. Structured counseling facilitated choice of contraceptive method for most women, leading to changes in women's selection of a CHC method. © 2011 Nordic Federation of Societies of Obstetrics and Gynecology.


Bitzer J.,University of Basel | Gemzell-Danielsson K.,Karolinska University Hospital | Roumen F.,Atrium Medical | Marintcheva-Petrova M.,Biostatistics and Research Decision science | And 2 more authors.
European Journal of Contraception and Reproductive Health Care | Year: 2012

Objectives To encourage healthcare professionals to counsel women seeking combined hormonal contraceptives (CHCs) about alternative CHCs and to study the influence of counselling on women's selection of CHCs. Methods Women (1540 years old) in 11 countries who consulted HCPs about CHCs were counselled about the pill, transdermal patch, and vaginal ring. Both the HCPs and the women completed questionnaires. Results Of women who were counselled (n = 18,787), 47% selected another CHC method than originally planned. One in four who intended to use the pill chose another method (16% chose the patch; 65% chose the ring). In total, patch use increased from 5% 8% (difference = 3.7% [97.5% CI: 3.34.2]; p < 0.0001). Ring use nearly quadrupled from 8% 30% (difference = 21.7% [97.5% CI: 21.022.5]; p < 0.0001). Nearly all women who were undecided prior to counselling selected a method after counselling. Selection of the pill increased most in Russia (+ 11%) and Sweden (+ 5%); patch selection was greatest in Russia (+ 7%) and Israel (+ 6%); ring use increased most in Ukraine and in the Czech Republic and Slovakia (+ 36%). Conclusions Counselling increases use of alternative CHCs, such as the patch and the ring. Considerable differences between countries were noted. © 2012 The European Society of Contraception and Reproductive Health.


Griesinger G.,University of Lübeck | Shapiro D.B.,Reproductive Biology Associates | Kolibianakis E.M.,Aristotle University of Thessaloniki | Witjes H.,Biostatistics and Research Decision science | Mannaerts B.M.,Merck And Co.
Reproductive BioMedicine Online | Year: 2011

The association between endogenous LH concentrations during ovarian stimulation in a gonadotrophin-releasing hormone (GnRH) antagonist protocol and pregnancy likelihood was examined in a large combined analysis of individualized patient data obtained after treatment with recombinant FSH and a GnRH antagonist prior to IVF/intracytoplasmic sperm injection. Data from 1764 patients from six randomized controlled trials were pooled for retrospective analysis. Ongoing pregnancy and miscarriage rates for patients stratified by LH percentiles were assessed. Patients in the lowest LH quartile (P75). With adjustment for identified predictive factors of pregnancy, estimated odds ratios (95% confidence interval) for ongoing pregnancy for LH categories P75 versus ≤P75 and P75 were 0.96 (0.75-1.22), 1.13 (0.88-1.45) and 0.89 (0.66-1.21) on stimulation day 8, and 0.96 (0.76-1.21), 1.03 (0.82-1.30) and 0.95 (0.72-1.26) on the day of human chorionic gonadotrophin, respectively. No significant differences in pregnancy or miscarriage rates between the LH categories were observed. Endogenous LH concentrations have no association with the likelihood of ongoing pregnancy in women undergoing ovarian stimulation using a recombinant FSH/GnRH antagonist protocol. Circulating concentrations of LH are suppressed during ovarian stimulation for IVF/intracytoplasmic sperm injection with either gonadotrophin-releasing hormone (GnRH) agonists or antagonists to prevent premature LH rises. The association between circulating LH concentrations during ovarian stimulation and the likelihood of pregnancy was examined in a large combined analysis of individualized patient data obtained after treatment with recombinant FSH to stimulate multifollicular development and a GnRH antagonist (ganirelix) to prevent LH surges. Data from 1764 patients from six randomized controlled trials were pooled for retrospective analysis. Patients were divided into three groups based on their circulating LH concentrations being either low, normal or high on stimulation day 8 and on the day of human chorionic gonadotrophin (HCG) administration, and their ongoing pregnancy and miscarriage rates were calculated. Patients with low LH concentrations were in general younger, had a higher ovarian reserve and more retrieved eggs than patients with high LH concentrations. With adjustment for factors known to affect pregnancy, the chance of ongoing pregnancy was not lower for patients with low or high LH concentrations on stimulation day 8 or day of HCG administration. No significant differences in miscarriage rates between the LH categories were observed either. This combined analysis confirms that the concentrations of circulating LH during GnRH antagonist treatment do not affect the likelihood of ongoing pregnancy in women undergoing ovarian stimulation with recombinant FSH. © 2011, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.


Fletcher C.,Amgen | Driessen S.,Abbott Laboratories | Burger H.U.,Hoffmann-La Roche | Gerlinger C.,Bayer AG | And 2 more authors.
Pharmaceutical Statistics | Year: 2013

The European Federation of Statisticians in the Pharmaceutical Industry (EFSPI) believes access to clinical trial data should be implemented in a way that supports good research, avoids misuse of such data, lies within the scope of the original informed consent and fully protects patient confidentiality. In principle, EFSPI supports responsible data sharing. EFSPI acknowledges it is in the interest of patients that their data are handled in a strictly confidential manner to avoid misuse under all possible circumstances. It is also in the interest of the altruistic nature of patients participating in trials that such data will be used for further development of science as much as possible applying good statistical principles. This paper summarises EFSPI's position on access to clinical trial data. The position was developed during the European Medicines Agency (EMA) advisory process and before the draft EMA policy on publication and access to clinical trial data was released for consultation; however, the EFSPI's position remains unchanged following the release of the draft policy. Finally, EFSPI supports a need for further guidance to be provided on important technical aspects relating to re-analyses and additional analyses of clinical trial data, for example, multiplicity, meta-analysis, subgroup analyses and publication bias. Copyright © 2013 John Wiley & Sons, Ltd. Copyright © 2013 John Wiley & Sons, Ltd.


Cammu G.,Onze Lieve Vrouw Ziekenhuis | De Kam P.-J.,Early Clinical Research and Experimental Medicine ECREM | De Graeve K.,Onze Lieve Vrouw Ziekenhuis | Van Den Heuvel M.,Early Clinical Research and Experimental Medicine ECREM | And 5 more authors.
British Journal of Anaesthesia | Year: 2010

Background. Re-intubation and re-operation may occasionally be required after neuromuscular block (NMB) reversal. This study evaluated block onset times of a second dose of rocuronium (1.2 mg kg-1) after sugammadex reversal of rocuronium 0.6 mg kg-1.MethodsIn this open-label study of healthy anaesthetized volunteers, subjects received rocuronium 0.6 mg kg -1, were antagonized at 1-2 post-tetanic counts with sugammadex 4.0 mg kg-1, and received rocuronium 1.2 mg kg-1 at 5, 7.5, 10, 15, 20, 22.5, 25, 27.5, 30, 45, or 60 min after sugammadex. Spontaneous recovery occurred after repeat rocuronium dose. Primary endpoints were the onset time of maximal block (time to lowest T1 value reached) and the clinical duration of block (until T1=25) after repeat rocuronium dose.ResultsSixteen subjects were included. For subjects receiving rocuronium 1.2 mg kg-1 5 min after sugammadex (n=6), mean (sd) onset time (to T1=0) was 3.06 (0.97) min; range, 1.92-4.72 min. For repeat dose time points ≥25 min (n=5), mean onset was faster (1.73 min) than for repeat doses <25 min (3.09 min) after sugammadex. The duration of block ranged from 17.7 min (rocuronium 5 min after sugammadex) to 46 min (repeat dose at 45 min). Mean duration was 24.8 min for repeat dosing <25 min vs 38.2 min for repeat doses ≥25 min.ConclusionsRapid re-onset of NMB occurred after repeat dose of rocuronium 1.2 mg kg-1 as early as 5 min after sugammadex in healthy volunteers. Re-onset of block took longer if second rocuronium dose was <25 min after sugammadex. The duration of action of second rocuronium dose increased with later repeat dose time points. © The Author 2010. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.


Doody K.J.,Center for Assisted Reproduction | Devroey P.,Universitair Ziekenhuis Brussel | Leader A.,University of Ottawa | Witjes H.,Biostatistics and Research Decision science | Mannaerts B.M.,Global Clinical Research
Reproductive BioMedicine Online | Year: 2011

The relationship between endogenous LH concentrations and ongoing pregnancy rates among normogonadotrophic patients undergoing ovarian stimulation in a gonadotrophin-releasing hormone antagonist protocol were examined. In the Engage trial, 1506 patients received corifollitropin alfa (150 μg) or daily recombinant FSH (rFSH) (200 IU) for the first 7 days of stimulation with 0.25 mg ganirelix from stimulation day 5. Patients were retrospectively stratified by serum LH percentiles (<25th, 25th-75th and >75th) on stimulation day 8 and day of human chorionic gonadotrophin administration. Odds ratios (OR) with and without adjustment for predictive factors for ongoing pregnancy were estimated. LH concentration was not associated with pregnancy rates in either treatment arm, in contrast to ovarian response and serum progesterone. With adjustment for these predictors and age, OR (95% confidence interval) for ongoing pregnancy on stimulation day 8 for LH categories P75 versus ≤P75 and P75 were 0.75 (0.53-1.06), 1.26 (0.87-1.83) and 0.70 (0.46-1.09) in the corifollitropin alfa arm and 0.80 (0.54-1.17), 1.28 (0.87-1.87) and 0.73 (0.46-1.16) in the rFSH arm respectively. There was also no significant difference in pregnancy rates between LH categories on day of human chorionic gonadotrophin administration with either treatment. During ovarian stimulation for IVF/intracytoplasmic sperm injection, circulating concentrations of LH should not become too high or too low as the development of mature eggs and the likelihood of ongoing pregnancy may be negatively affected. Gonadotrophin-releasing hormone (GnRH) analogues are applied to prevent premature LH rises but certain regimens may result in relatively low circulating LH concentrations. To examine the relationship between circulating LH concentrations and ongoing pregnancy rates in a GnRH antagonist protocol, data from a large randomized trial, Engage, were retrospectively analysed. In this trial, 1506 patients received corifollitropin alfa or daily recombinant FSH for the first 7 days of stimulation and ganirelix (a GnRH antagonist) from stimulation day 5 onwards. Patients were grouped by their LH concentration (low, normal or high) on stimulation day 8 and the day of human chorionic gonadotrophin (HCG) administration to trigger final egg maturation. The chance of ongoing pregnancy by LH category, with or without adjustment for other factors affecting pregnancy was calculated. There was no significant difference in the chance of pregnancy between patients in the different LH categories, regardless of the day of assessment or the treatment group. In contrast, circulating progesterone (another hormone produced by mature follicles) and the number of eggs retrieved clearly affected the chance of pregnancy. These analyses showed that ongoing pregnancy rates are not influenced by either low or high circulating LH concentrations when using a GnRH antagonist protocol. © 2011, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.


Andersen A.N.,Copenhagen University | Witjes H.,Biostatistics and Research Decision science | Gordon K.,Merck And Co. | Mannaerts B.,Global Clinical Research
Human Reproduction | Year: 2011

Background: Prediction of ovarian response prior to the first controlled ovarian stimulation (COS) cycle is useful in determining the optimal starting dose of recombinant FSH (rFSH). However, potentially predictive factors may be subject to inter-cycle variability and many patients are pre-treated with oral contraceptives (OC) for scheduling purposes. Our objective was to determine predictive factors of ovarian response for patients undergoing COS with rFSH in a gonadotrophin-releasing hormone antagonist protocol and to determine the inter-cycle variability of these factors.Methods: In this multinational trial, 442 patients were randomized to receive either OC treatment or no treatment prior to their first COS cycle. For candidate predictive factors, patient characteristics were collected at screening, and endocrine and sonographic data were collected during the early follicular phase of the two subsequent cycles. A treatment regimen of 200 IU rFSH and 0.25 mg ganirelix was applied during the second cycle. Predictive factors of ovarian response and of too low (<6 oocytes) or too high (>18 oocytes) ovarian responses were determined using stepwise linear regression and stepwise logistic regression, respectively.Results: Anti-Mllerian hormone (AMH) and basal FSH were statistically significant predictors of the number of oocytes retrieved and of an excessive ovarian response. For low ovarian response, AMH was the only significant predictive factor. In the non-OC group, the predictive value was higher than in the OC group and higher at the early follicular phase of the stimulation cycle than of the previous cycle. The inter-cycle variation for AMH was low compared with the inter-cycle variation of other hormones. Between the two groups, there were no differences in the number or quality of embryos obtained or transferred, but the implantation rate was significantly lower in the OC group (24.1 versus 30.1, P 0.03), resulting in an ongoing pregnancy rate of 26.3 compared with 35.7 in the non-OC group (P 0.05). Conclusions: The best predictive model of ovarian response was in the non-OC group and included both AMH and basal FSH determined at the early follicular phase of the stimulation cycle. In the proceeding cycle, AMH alone had sufficient predictive value since it was not affected by inter-cycle variability or OC pretreatment.Clinical trial identifier: NCT00778999. © 2011 The Author. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.


Cammu G.,Onze Lieve Vrouw Ziekenhuis | Van Vlem B.,Renal Unit | Van Den Heuvel M.,Clinical PKPD | Stet L.,CNS Global Clinical Trial Management | And 3 more authors.
British Journal of Anaesthesia | Year: 2012

Background. Renal excretion is the primary route for the elimination of sugammadex. We evaluated the dialysability of sugammadex and the sugammadexrocuronium complex in patients with severe renal impairment in the intensive care unit (ICU). Methods. Six patients in the ICU with acute severe renal impairment received general anaesthesia for transoesophageal echocardiography, to replace their tracheal tubes, or for bronchoscopy. Five of the six patients were in the ICU after cardiac/vascular surgery and one for pneumonia-induced respiratory failure. They all received rocuronium 0.6 mg kg -1, followed 15 min later by sugammadex 4.0 mg kg -1. Two patients were studied for two dialysis episodes and four patients for four episodes. Rocuronium and sugammadex concentrations were measured in plasma and dialysate at several time points before, during, and after high-flux dialysis. Dialysis clearance in plasma and dialysate, and reduction ratio (RR) (the extent of the plasma concentration reduction at the end of a dialysis episode when compared with before dialysis) were calculated for each dialysis episode. Results. Dialysis episodes lasted on average 6 h. Observed RRs indicated mean reductions of 69% and 75% in the plasma concentrations of sugammadex and rocuronium, respectively, during the first dialysis episode. Reductions were around 50% during sequential dialysis episodes. On average, dialysis clearance of sugammadex and rocuronium in blood was 78 and 89 ml min -1, respectively. Conclusions. Haemodialysis using a high-flux dialysis method is effective in removing sugammadex and the sugammadexrocuronium complex in patients with severe renal impairment. © 2012 The Author. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.

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