Fabian Tibaldi - Academia.edu (original) (raw)

Papers by Fabian Tibaldi

Research paper thumbnail of Methodology of the validation of surrogate endpoints in multiple randomized experiments

Research paper thumbnail of A 5-week study of the pharmacokinetics and pharmacodynamics of LY2189265, a novel, long-acting glucagon-like peptide-1 analogue, in patients with type 2 diabetes

Diabetes, Obesity and Metabolism, Mar 24, 2011

Aim: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of LY2189265 ... more Aim: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of LY2189265 (LY), a novel, long-acting glucagen-like peptide-1 analogue, administered once weekly to subjects with type 2 diabetes. Methods: This was a placebo-controlled, parallel-group, subject-and investigator-blind study of LY in subjects (N = 43) with type 2 diabetes mellitus controlled with diet and exercise alone or with a single oral antidiabetic medication. Subjects taking metformin or thiazolidinediones continued on their therapy. Subjects receiving sulfonylurea, acarbose, repaglinide or nateglinide were switched to metformin prior to enrollment. Subjects received five once-weekly doses of 0.05, 0.3, 1, 3, 5 or 8 mg. Effects on glucose, insulin and C-peptide concentrations were determined during fasting and following standard test meals. The pharmacokinetics of LY and its effects on HBA1c, glucagon, body weight, gastric emptying and safety parameters were assessed. Results: Once-weekly administration of LY significantly reduced (p < 0.01) fasting plasma glucose, 2-h post-test meal postprandial glucose and area under the curve (AUC) of glucose after test meals at doses ≥1 mg. These effects were seen after the first dose and were sustained through the weekly dosing cycle. Most doses produced statistically significant increases in insulin and C-peptide AUC when normalized for glucose AUC. Statistically significant reductions in HBA1c were observed for all dose groups except 0.3 mg. The most commonly reported adverse effects (AEs) were nausea (35 events), headache (20 events), vomiting (18 events) and diarrhoea (8 events). Conclusions: LY showed improvement in fasting and postprandial glycaemic parameters when administered once weekly in subjects with type 2 diabetes. The pharmacokinetics and safety profiles also support further investigation of this novel agent.

Research paper thumbnail of Principal surrogates in context of high vaccine efficacy

Statistical Communications in Infectious Diseases, 2021

Objectives: The use of correlates of protection (CoPs) in vaccination trials offers significant a... more Objectives: The use of correlates of protection (CoPs) in vaccination trials offers significant advantages as useful clinical endpoint substitutes. Vaccines with very high vaccine efficacy (VE) are documented in the literature (95% or above). Callegaro, A., and F. Tibaldi. 2019. "Assessing Correlates of Protection in Vaccine Trials: Statistical Solutions in the Context of High Vaccine Efficacy." BMC Medical Research Methodology 19: 47 showed that the rare infections observed in the vaccinated groups of these trials poses challenges when applying conventionally-used statistical methods for CoP assessment such as the Prentice criteria and metaanalysis. The objective of this work is to investigate the impact of this problem on another statistical method for the assessment of CoPs called Principal stratification. Methods: We perform simulation experiments to investigate the effect of high vaccine efficacy on the performance of the Principal Stratification approach. Results: Similarly to the Prentice framework, simulation results show that the power of the Principal Stratification approach decreases when the VE grows. Conclusions: It can be challenging to validate principal surrogates (and statistical surrogates) for vaccines with very high vaccine efficacy.

Research paper thumbnail of Assessing correlates of protection in vaccine trials: statistical solutions in the context of high vaccine efficacy

BMC Medical Research Methodology, Mar 6, 2019

Background: The use of correlates of protection (CoPs) in vaccination trials offers significant a... more Background: The use of correlates of protection (CoPs) in vaccination trials offers significant advantages as useful clinical endpoint substitutes. Vaccines with very high vaccine efficacy (VE) are documented in the literature (VE ≥95%). The rare events (number of infections) observed in the vaccinated groups of these trials posed challenges when applying conventionally-used statistical methods for CoP assessment. In this paper, we describe the nature of these challenges, and propose easy-to-implement and uniquely-tailored statistical solutions for the assessment of CoPs in the specific context of high VE. Methods: The Prentice criteria and meta-analytic frameworks are standard statistical methods for assessing vaccine CoPs, but can be problematic in high VE cases due to the rare events data available. As a result, lack of fit and the problem of infinite estimates may arise, in the former and latter methods respectively. The use of flexible models within the Prentice framework, and penalized-likelihood methods to solve the issue of infinite estimates can improve the performance of both methods in high VE settings. Results: We have 1) devised flexible non-linear models to counteract the Prentice framework lack of fit, providing sufficient statistical power to the method, and 2) proposed the use of penalised likelihood approaches to make the meta-analytic framework applicable on randomized subgroups, such as regions. The performance of the proposed methods for high VE cases was evaluated by running simulations. Conclusions: As vaccines with high efficacy are documented in the literature, there is a need to identify effective statistical solutions to assess CoPs. Our proposed adaptations are straightforward and improve the performance of conventional statistical methods for high VE data, leading to more reliable CoP assessments in the context of high VE settings.

Research paper thumbnail of Hemagglutination Inhibition Antibody Titers as a Correlate of Protection Against Seasonal A/H3N2 Influenza Disease

Open Forum Infectious Diseases, Apr 1, 2015

Background. To investigate the relationship between hemagglutinin-inhibition (HI) antibody levels... more Background. To investigate the relationship between hemagglutinin-inhibition (HI) antibody levels to the risk of influenza disease, we conducted a correlate of protection analysis using pooled data from previously published randomized trials. Methods. Data on the occurrence of laboratory-confirmed influenza and HI levels pre-and postvaccination were analyzed from 4 datasets: 3 datasets included subjects aged <65 years who received inactivated trivalent influenza vaccine (TIV) or placebo, and 1 dataset included subjects aged ≥65 years who received AS03-adjuvanted TIV (AS03-TIV) or TIV. A logistic model was used to evaluate the relationship between the postvaccination titer of A/H3N2 HI antibodies and occurrence of A/H3N2 disease. We then built a receiver-operating characteristic curve to identify a potential cutoff titer between protection and no protection. Results. The baseline odds ratio of A/H3N2 disease was higher for subjects aged ≥65 years than <65 years and higher in seasons of strong epidemic intensity than moderate or low intensity. Including age and epidemic intensity as covariates, a 4-fold increase in titer was associated with a 2-fold decrease in the risk of A/H3N2 disease. Conclusions. The modeling exercise confirmed a relationship between A/H3N2 disease and HI responses, but it did not allow an evaluation of the predictive power of the HI response.

Research paper thumbnail of Indication for thresholds of chromosome non-disjunction versus chromosome lagging induced by spindle inhibitors <i>in vitro</i> in human lymphocytes

Mutagenesis, 1997

Risk assessment from exposure to spindle inhibitors should take into account the possibility of t... more Risk assessment from exposure to spindle inhibitors should take into account the possibility of threshold concentrationresponse curves for aneuploidy induction. We analysed concentration-dependent induction of chromosome nondisjunction by well known spindle poisons (colchicine, carbendazim, mebendazole and nocodazole) and a reference clastogen, methyl methanesulphonate (MMS) in vitro in human lymphocytes; and integrated these findings with earlier results of chromosome loss in micronuclei. Chromosome non-disjunction was estimated on cytokinesis-blocked lymphocytes after simultaneous fluorescent in situ hybridization labelling with two chromosome-specific centromeric probes (chromosomes 1 and 17). The frequencies of spontaneous non-disjunction showed important inter-individual variations and were surprisingly high (7.04-15.39%). Lower concentrations of aneugens did not induce a statistically significant increase of non-disjunction frequencies over the respective control levels, whereas higher concentrations clearly induced a concentration-dependent increase in the non-disjunction frequencies with the four aneugens tested. On the contrary, even at high concentrations, MMS induced a slight increase in the frequency of non-disjunction but without being statistically significant when compared with the control frequencies. We estimated the inflection points, the first statistically significant concentrations, the last nonstatistically significant concentrations and the number of events from concentration-response curves of chromosome non-disjunction and chromosome loss. A threshold-type of concentration-response for non-disjunction is highly probable for colchicine and nocodazole. For carbendazim and mebendazole the inflection point fell above the first statistically significant concentrations. But since it is obvious from dose-response curves where the inflection point/ threshold lies, it appears that the model might be picking up some irregularities (possibly due to experimental variability in the dose-response curve at concentrations greater than the threshold). For accurate estimation of the threshold, analysis of more concentrations or more cells might be needed. Our data strongly indicate that in cultured human lymphocytes chromosome non-disjunction is a major mechanism of aneuploidy induction by spindle inhibitors and since non-disjunction occurs at lower concentration than chromosome loss, the aneuploidy threshold should be estimated on the basis of non-disjunction rather than on micronuclei frequencies (chromosome loss).

Research paper thumbnail of The authors replied as follows

Research paper thumbnail of Copyright © The British Psychological Society

Reproduction in any form (including the internet) is prohibited without prior permission from the... more Reproduction in any form (including the internet) is prohibited without prior permission from the Society Expectancies, not aroma, explain impact of lavender aromatherapy on psychophysiological indices of relaxation in young healthy women Siobhán Howard and Brian M. Hughes*

Research paper thumbnail of A/H3N2 influenza disease

Research paper thumbnail of Implementation of a Phase 1 Adaptive Clinical Trial in a Treatment of Type 2 Diabetes

Drug Information Journal, 2008

Research paper thumbnail of Methodology of the validation of surrogate endpoints in multiple randomized experiments

Research paper thumbnail of Effects of varying antigens and adjuvant systems on the immunogenicity and safety of investigational tetravalent human oncogenic papillomavirus vaccines: results from two randomized trials

Background: A prophylactic human papillomavirus (HPV) vaccine targeting oncogenic HPV types in ad... more Background: A prophylactic human papillomavirus (HPV) vaccine targeting oncogenic HPV types in addition to HPV-16 and-18 may broaden protection against cervical cancer. Two Phase I/II, randomized, controlled studies were conducted to compare the immunogenicity and safety of investigational tetravalent HPV L1 virus-like particle (VLP) vaccines, containing VLPs from two additional oncogenic genotypes, with the licensed HPV-16/18 AS04-adjuvanted vaccine (control) in healthy 18-25 year-old women. Methods: In one trial (NCT00231413), subjects received control or one of 6 tetravalent HPV-16/18/31/45 AS04 vaccine formulations at months (M) 0,1,6. In a second trial (NCT00478621), subjects received control or one of 5 tetravalent HPV-16/18/33/58 vaccines formulated with different adjuvant systems (AS04, AS01 or AS02), administered on different schedules (M0,1,6 or M0,3 or M0,6). Results: One month after the third injection (Month 7), there was a consistent trend for lower anti-HPV-16 and-18 geometric mean antibody titers (GMTs) for tetravalent AS04-adjuvanted vaccines compared with control. GMTs were statistically significantly lower for an HPV-16/18/31/45 AS04 vaccine containing

Research paper thumbnail of Joint detection of important biomarkers and optimal dose–response model using penalties

Statistics in Medicine, 2007

We propose a method to jointly detect influential biomarkers and estimate how they change with do... more We propose a method to jointly detect influential biomarkers and estimate how they change with dose. The assessment is made in dose‐ranging trials collecting multiple outcomes for efficacy, safety, pharmacokinetics or pharmacodynamics. We regress all these outcomes versus a non‐parametric transformation of the dose. The regression coefficients and the parameters from the dose–response model are simultaneously estimated using a penalized alternating least‐squares method. We illustrate the technique with a phase I clinical trial and a metabonomic experiment in rats. Copyright © 2007 John Wiley & Sons, Ltd.

Research paper thumbnail of Linear Categorical Marginal Modeling of Solicited Symptoms in Vaccine Clinical Trials

Statistics in Biopharmaceutical Research, 2013

Research paper thumbnail of Age of Attainment of Developmental Milestones in Healthy Argentinian Children Less Than Six Years of Age 6

Research paper thumbnail of Evaluation of a National Survey on Child Psychomotor Development, Whith Participation of Pediatricians

Research paper thumbnail of Hemagglutination Inhibition Antibody Titers as a Correlate of Protection for Inactivated Influenza Vaccines in Children

Pediatric Infectious Disease Journal, 2011

Background: Pneumococcal disease is a major global cause of morbidity and mortality. This study e... more Background: Pneumococcal disease is a major global cause of morbidity and mortality. This study evaluated risk factors for mortality in children with pneumococcal meningitis and other invasive pneumococcal diseases (IPD). Methods: The study population included patients Ͻ15 years of age with laboratory-confirmed IPD and available outcome data between January 1, 2003 and December 31, 2005 as reported to a national laboratory-based surveillance program. Meningitis was defined by having pneumococcus identified from cerebrospinal fluid culture, while other IPD included patients with pneumococci identified from other normally sterile site specimens. Risk factors for mortality were evaluated using multivariable logistic regression. Results: A total of 2251 patients with IPD were reported from sentinel sites: 581 with laboratory-confirmed meningitis and 1670 with other IPD. The case-fatality ratio was 35% (205/581) among meningitis cases and 18% (300/1670) among other IPD cases (P Ͻ 0.001). Among individuals with available human immunodeficiency virus (HIV) status data, HIV coinfection was less likely among patients with meningitis compared with other IPD (74% ͓244/328͔ vs. 82% ͓880/1067͔ P Ͻ 0.001). On multivariable analysis, HIVinfected status (odds ratio ͓OR͔: 5.34, 95% confidence interval ͓CI͔: 2.32-12.29), Pitt bacteremia score Ն4 (OR: 3.08, 95% CI: 1.21-7.83) and age group Ͻ1 year (OR: 2.58, 95% CI: 1.21-5.51) were independent predictors of death among patients with meningitis. Among children with other IPD, malnutrition was an independent predictor of death while HIV infection was not independently associated with increased risk of death. Conclusions: Pneumococcal meningitis is associated with a high casefatality ratio among South African children and this is increased by HIV coinfection. Increasing access to antiretroviral therapy and a catch-up program for pneumococcal conjugate vaccine among HIV-infected and malnourished children could reduce this excess mortality.

Research paper thumbnail of Psychomotor development in Argentinean children aged 0-5 years

Paediatric and Perinatal Epidemiology, 2002

Research paper thumbnail of The organisation of a national survey for evaluating child psychomotor development in Argentina

Paediatric and Perinatal Epidemiology, 1997

SummaryA total of 211 selected paediatricians were invited to participate in a national survey de... more SummaryA total of 211 selected paediatricians were invited to participate in a national survey designed to evaluate the age of attainment of developmental milestones in children aged 0–5 years. Following a pilot study and a cascade training design, 61.1% of the paediatricians successfully completed the data collection on 139 developmental items. In the pilot study, there were more missing (not performed) items in children over one year of age, thus confirming the impression that paediatricians are more familiar with evaluating development in infants. However, in the age range 1–5 years, there were significantly fewer missing items in the gross motor area than in the other areas. Following a training programme and data editing and cleaning, a final sample of 3573 healthy, normal children was obtained. The impact of the training process was significant, in the sense that 3.5% of the items in children older than one year were not performed by the paediatricians before training, but thi...

Research paper thumbnail of Indication for thresholds of chromosome non-disjunction versus chromosome lagging induced by spindle inhibitors in vitro in human lymphocytes

Mutagenesis, 1997

Risk assessment from exposure to spindle inhibitors should take into account the possibility of t... more Risk assessment from exposure to spindle inhibitors should take into account the possibility of threshold concentrationresponse curves for aneuploidy induction. We analysed concentration-dependent induction of chromosome nondisjunction by well known spindle poisons (colchicine, carbendazim, mebendazole and nocodazole) and a reference clastogen, methyl methanesulphonate (MMS) in vitro in human lymphocytes; and integrated these findings with earlier results of chromosome loss in micronuclei. Chromosome non-disjunction was estimated on cytokinesis-blocked lymphocytes after simultaneous fluorescent in situ hybridization labelling with two chromosome-specific centromeric probes (chromosomes 1 and 17). The frequencies of spontaneous non-disjunction showed important inter-individual variations and were surprisingly high (7.04-15.39%). Lower concentrations of aneugens did not induce a statistically significant increase of non-disjunction frequencies over the respective control levels, whereas higher concentrations clearly induced a concentration-dependent increase in the non-disjunction frequencies with the four aneugens tested. On the contrary, even at high concentrations, MMS induced a slight increase in the frequency of non-disjunction but without being statistically significant when compared with the control frequencies. We estimated the inflection points, the first statistically significant concentrations, the last nonstatistically significant concentrations and the number of events from concentration-response curves of chromosome non-disjunction and chromosome loss. A threshold-type of concentration-response for non-disjunction is highly probable for colchicine and nocodazole. For carbendazim and mebendazole the inflection point fell above the first statistically significant concentrations. But since it is obvious from dose-response curves where the inflection point/ threshold lies, it appears that the model might be picking up some irregularities (possibly due to experimental variability in the dose-response curve at concentrations greater than the threshold). For accurate estimation of the threshold, analysis of more concentrations or more cells might be needed. Our data strongly indicate that in cultured human lymphocytes chromosome non-disjunction is a major mechanism of aneuploidy induction by spindle inhibitors and since non-disjunction occurs at lower concentration than chromosome loss, the aneuploidy threshold should be estimated on the basis of non-disjunction rather than on micronuclei frequencies (chromosome loss).

Research paper thumbnail of Methodology of the validation of surrogate endpoints in multiple randomized experiments

Research paper thumbnail of A 5-week study of the pharmacokinetics and pharmacodynamics of LY2189265, a novel, long-acting glucagon-like peptide-1 analogue, in patients with type 2 diabetes

Diabetes, Obesity and Metabolism, Mar 24, 2011

Aim: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of LY2189265 ... more Aim: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of LY2189265 (LY), a novel, long-acting glucagen-like peptide-1 analogue, administered once weekly to subjects with type 2 diabetes. Methods: This was a placebo-controlled, parallel-group, subject-and investigator-blind study of LY in subjects (N = 43) with type 2 diabetes mellitus controlled with diet and exercise alone or with a single oral antidiabetic medication. Subjects taking metformin or thiazolidinediones continued on their therapy. Subjects receiving sulfonylurea, acarbose, repaglinide or nateglinide were switched to metformin prior to enrollment. Subjects received five once-weekly doses of 0.05, 0.3, 1, 3, 5 or 8 mg. Effects on glucose, insulin and C-peptide concentrations were determined during fasting and following standard test meals. The pharmacokinetics of LY and its effects on HBA1c, glucagon, body weight, gastric emptying and safety parameters were assessed. Results: Once-weekly administration of LY significantly reduced (p < 0.01) fasting plasma glucose, 2-h post-test meal postprandial glucose and area under the curve (AUC) of glucose after test meals at doses ≥1 mg. These effects were seen after the first dose and were sustained through the weekly dosing cycle. Most doses produced statistically significant increases in insulin and C-peptide AUC when normalized for glucose AUC. Statistically significant reductions in HBA1c were observed for all dose groups except 0.3 mg. The most commonly reported adverse effects (AEs) were nausea (35 events), headache (20 events), vomiting (18 events) and diarrhoea (8 events). Conclusions: LY showed improvement in fasting and postprandial glycaemic parameters when administered once weekly in subjects with type 2 diabetes. The pharmacokinetics and safety profiles also support further investigation of this novel agent.

Research paper thumbnail of Principal surrogates in context of high vaccine efficacy

Statistical Communications in Infectious Diseases, 2021

Objectives: The use of correlates of protection (CoPs) in vaccination trials offers significant a... more Objectives: The use of correlates of protection (CoPs) in vaccination trials offers significant advantages as useful clinical endpoint substitutes. Vaccines with very high vaccine efficacy (VE) are documented in the literature (95% or above). Callegaro, A., and F. Tibaldi. 2019. "Assessing Correlates of Protection in Vaccine Trials: Statistical Solutions in the Context of High Vaccine Efficacy." BMC Medical Research Methodology 19: 47 showed that the rare infections observed in the vaccinated groups of these trials poses challenges when applying conventionally-used statistical methods for CoP assessment such as the Prentice criteria and metaanalysis. The objective of this work is to investigate the impact of this problem on another statistical method for the assessment of CoPs called Principal stratification. Methods: We perform simulation experiments to investigate the effect of high vaccine efficacy on the performance of the Principal Stratification approach. Results: Similarly to the Prentice framework, simulation results show that the power of the Principal Stratification approach decreases when the VE grows. Conclusions: It can be challenging to validate principal surrogates (and statistical surrogates) for vaccines with very high vaccine efficacy.

Research paper thumbnail of Assessing correlates of protection in vaccine trials: statistical solutions in the context of high vaccine efficacy

BMC Medical Research Methodology, Mar 6, 2019

Background: The use of correlates of protection (CoPs) in vaccination trials offers significant a... more Background: The use of correlates of protection (CoPs) in vaccination trials offers significant advantages as useful clinical endpoint substitutes. Vaccines with very high vaccine efficacy (VE) are documented in the literature (VE ≥95%). The rare events (number of infections) observed in the vaccinated groups of these trials posed challenges when applying conventionally-used statistical methods for CoP assessment. In this paper, we describe the nature of these challenges, and propose easy-to-implement and uniquely-tailored statistical solutions for the assessment of CoPs in the specific context of high VE. Methods: The Prentice criteria and meta-analytic frameworks are standard statistical methods for assessing vaccine CoPs, but can be problematic in high VE cases due to the rare events data available. As a result, lack of fit and the problem of infinite estimates may arise, in the former and latter methods respectively. The use of flexible models within the Prentice framework, and penalized-likelihood methods to solve the issue of infinite estimates can improve the performance of both methods in high VE settings. Results: We have 1) devised flexible non-linear models to counteract the Prentice framework lack of fit, providing sufficient statistical power to the method, and 2) proposed the use of penalised likelihood approaches to make the meta-analytic framework applicable on randomized subgroups, such as regions. The performance of the proposed methods for high VE cases was evaluated by running simulations. Conclusions: As vaccines with high efficacy are documented in the literature, there is a need to identify effective statistical solutions to assess CoPs. Our proposed adaptations are straightforward and improve the performance of conventional statistical methods for high VE data, leading to more reliable CoP assessments in the context of high VE settings.

Research paper thumbnail of Hemagglutination Inhibition Antibody Titers as a Correlate of Protection Against Seasonal A/H3N2 Influenza Disease

Open Forum Infectious Diseases, Apr 1, 2015

Background. To investigate the relationship between hemagglutinin-inhibition (HI) antibody levels... more Background. To investigate the relationship between hemagglutinin-inhibition (HI) antibody levels to the risk of influenza disease, we conducted a correlate of protection analysis using pooled data from previously published randomized trials. Methods. Data on the occurrence of laboratory-confirmed influenza and HI levels pre-and postvaccination were analyzed from 4 datasets: 3 datasets included subjects aged <65 years who received inactivated trivalent influenza vaccine (TIV) or placebo, and 1 dataset included subjects aged ≥65 years who received AS03-adjuvanted TIV (AS03-TIV) or TIV. A logistic model was used to evaluate the relationship between the postvaccination titer of A/H3N2 HI antibodies and occurrence of A/H3N2 disease. We then built a receiver-operating characteristic curve to identify a potential cutoff titer between protection and no protection. Results. The baseline odds ratio of A/H3N2 disease was higher for subjects aged ≥65 years than <65 years and higher in seasons of strong epidemic intensity than moderate or low intensity. Including age and epidemic intensity as covariates, a 4-fold increase in titer was associated with a 2-fold decrease in the risk of A/H3N2 disease. Conclusions. The modeling exercise confirmed a relationship between A/H3N2 disease and HI responses, but it did not allow an evaluation of the predictive power of the HI response.

Research paper thumbnail of Indication for thresholds of chromosome non-disjunction versus chromosome lagging induced by spindle inhibitors <i>in vitro</i> in human lymphocytes

Mutagenesis, 1997

Risk assessment from exposure to spindle inhibitors should take into account the possibility of t... more Risk assessment from exposure to spindle inhibitors should take into account the possibility of threshold concentrationresponse curves for aneuploidy induction. We analysed concentration-dependent induction of chromosome nondisjunction by well known spindle poisons (colchicine, carbendazim, mebendazole and nocodazole) and a reference clastogen, methyl methanesulphonate (MMS) in vitro in human lymphocytes; and integrated these findings with earlier results of chromosome loss in micronuclei. Chromosome non-disjunction was estimated on cytokinesis-blocked lymphocytes after simultaneous fluorescent in situ hybridization labelling with two chromosome-specific centromeric probes (chromosomes 1 and 17). The frequencies of spontaneous non-disjunction showed important inter-individual variations and were surprisingly high (7.04-15.39%). Lower concentrations of aneugens did not induce a statistically significant increase of non-disjunction frequencies over the respective control levels, whereas higher concentrations clearly induced a concentration-dependent increase in the non-disjunction frequencies with the four aneugens tested. On the contrary, even at high concentrations, MMS induced a slight increase in the frequency of non-disjunction but without being statistically significant when compared with the control frequencies. We estimated the inflection points, the first statistically significant concentrations, the last nonstatistically significant concentrations and the number of events from concentration-response curves of chromosome non-disjunction and chromosome loss. A threshold-type of concentration-response for non-disjunction is highly probable for colchicine and nocodazole. For carbendazim and mebendazole the inflection point fell above the first statistically significant concentrations. But since it is obvious from dose-response curves where the inflection point/ threshold lies, it appears that the model might be picking up some irregularities (possibly due to experimental variability in the dose-response curve at concentrations greater than the threshold). For accurate estimation of the threshold, analysis of more concentrations or more cells might be needed. Our data strongly indicate that in cultured human lymphocytes chromosome non-disjunction is a major mechanism of aneuploidy induction by spindle inhibitors and since non-disjunction occurs at lower concentration than chromosome loss, the aneuploidy threshold should be estimated on the basis of non-disjunction rather than on micronuclei frequencies (chromosome loss).

Research paper thumbnail of The authors replied as follows

Research paper thumbnail of Copyright © The British Psychological Society

Reproduction in any form (including the internet) is prohibited without prior permission from the... more Reproduction in any form (including the internet) is prohibited without prior permission from the Society Expectancies, not aroma, explain impact of lavender aromatherapy on psychophysiological indices of relaxation in young healthy women Siobhán Howard and Brian M. Hughes*

Research paper thumbnail of A/H3N2 influenza disease

Research paper thumbnail of Implementation of a Phase 1 Adaptive Clinical Trial in a Treatment of Type 2 Diabetes

Drug Information Journal, 2008

Research paper thumbnail of Methodology of the validation of surrogate endpoints in multiple randomized experiments

Research paper thumbnail of Effects of varying antigens and adjuvant systems on the immunogenicity and safety of investigational tetravalent human oncogenic papillomavirus vaccines: results from two randomized trials

Background: A prophylactic human papillomavirus (HPV) vaccine targeting oncogenic HPV types in ad... more Background: A prophylactic human papillomavirus (HPV) vaccine targeting oncogenic HPV types in addition to HPV-16 and-18 may broaden protection against cervical cancer. Two Phase I/II, randomized, controlled studies were conducted to compare the immunogenicity and safety of investigational tetravalent HPV L1 virus-like particle (VLP) vaccines, containing VLPs from two additional oncogenic genotypes, with the licensed HPV-16/18 AS04-adjuvanted vaccine (control) in healthy 18-25 year-old women. Methods: In one trial (NCT00231413), subjects received control or one of 6 tetravalent HPV-16/18/31/45 AS04 vaccine formulations at months (M) 0,1,6. In a second trial (NCT00478621), subjects received control or one of 5 tetravalent HPV-16/18/33/58 vaccines formulated with different adjuvant systems (AS04, AS01 or AS02), administered on different schedules (M0,1,6 or M0,3 or M0,6). Results: One month after the third injection (Month 7), there was a consistent trend for lower anti-HPV-16 and-18 geometric mean antibody titers (GMTs) for tetravalent AS04-adjuvanted vaccines compared with control. GMTs were statistically significantly lower for an HPV-16/18/31/45 AS04 vaccine containing

Research paper thumbnail of Joint detection of important biomarkers and optimal dose–response model using penalties

Statistics in Medicine, 2007

We propose a method to jointly detect influential biomarkers and estimate how they change with do... more We propose a method to jointly detect influential biomarkers and estimate how they change with dose. The assessment is made in dose‐ranging trials collecting multiple outcomes for efficacy, safety, pharmacokinetics or pharmacodynamics. We regress all these outcomes versus a non‐parametric transformation of the dose. The regression coefficients and the parameters from the dose–response model are simultaneously estimated using a penalized alternating least‐squares method. We illustrate the technique with a phase I clinical trial and a metabonomic experiment in rats. Copyright © 2007 John Wiley & Sons, Ltd.

Research paper thumbnail of Linear Categorical Marginal Modeling of Solicited Symptoms in Vaccine Clinical Trials

Statistics in Biopharmaceutical Research, 2013

Research paper thumbnail of Age of Attainment of Developmental Milestones in Healthy Argentinian Children Less Than Six Years of Age 6

Research paper thumbnail of Evaluation of a National Survey on Child Psychomotor Development, Whith Participation of Pediatricians

Research paper thumbnail of Hemagglutination Inhibition Antibody Titers as a Correlate of Protection for Inactivated Influenza Vaccines in Children

Pediatric Infectious Disease Journal, 2011

Background: Pneumococcal disease is a major global cause of morbidity and mortality. This study e... more Background: Pneumococcal disease is a major global cause of morbidity and mortality. This study evaluated risk factors for mortality in children with pneumococcal meningitis and other invasive pneumococcal diseases (IPD). Methods: The study population included patients Ͻ15 years of age with laboratory-confirmed IPD and available outcome data between January 1, 2003 and December 31, 2005 as reported to a national laboratory-based surveillance program. Meningitis was defined by having pneumococcus identified from cerebrospinal fluid culture, while other IPD included patients with pneumococci identified from other normally sterile site specimens. Risk factors for mortality were evaluated using multivariable logistic regression. Results: A total of 2251 patients with IPD were reported from sentinel sites: 581 with laboratory-confirmed meningitis and 1670 with other IPD. The case-fatality ratio was 35% (205/581) among meningitis cases and 18% (300/1670) among other IPD cases (P Ͻ 0.001). Among individuals with available human immunodeficiency virus (HIV) status data, HIV coinfection was less likely among patients with meningitis compared with other IPD (74% ͓244/328͔ vs. 82% ͓880/1067͔ P Ͻ 0.001). On multivariable analysis, HIVinfected status (odds ratio ͓OR͔: 5.34, 95% confidence interval ͓CI͔: 2.32-12.29), Pitt bacteremia score Ն4 (OR: 3.08, 95% CI: 1.21-7.83) and age group Ͻ1 year (OR: 2.58, 95% CI: 1.21-5.51) were independent predictors of death among patients with meningitis. Among children with other IPD, malnutrition was an independent predictor of death while HIV infection was not independently associated with increased risk of death. Conclusions: Pneumococcal meningitis is associated with a high casefatality ratio among South African children and this is increased by HIV coinfection. Increasing access to antiretroviral therapy and a catch-up program for pneumococcal conjugate vaccine among HIV-infected and malnourished children could reduce this excess mortality.

Research paper thumbnail of Psychomotor development in Argentinean children aged 0-5 years

Paediatric and Perinatal Epidemiology, 2002

Research paper thumbnail of The organisation of a national survey for evaluating child psychomotor development in Argentina

Paediatric and Perinatal Epidemiology, 1997

SummaryA total of 211 selected paediatricians were invited to participate in a national survey de... more SummaryA total of 211 selected paediatricians were invited to participate in a national survey designed to evaluate the age of attainment of developmental milestones in children aged 0–5 years. Following a pilot study and a cascade training design, 61.1% of the paediatricians successfully completed the data collection on 139 developmental items. In the pilot study, there were more missing (not performed) items in children over one year of age, thus confirming the impression that paediatricians are more familiar with evaluating development in infants. However, in the age range 1–5 years, there were significantly fewer missing items in the gross motor area than in the other areas. Following a training programme and data editing and cleaning, a final sample of 3573 healthy, normal children was obtained. The impact of the training process was significant, in the sense that 3.5% of the items in children older than one year were not performed by the paediatricians before training, but thi...

Research paper thumbnail of Indication for thresholds of chromosome non-disjunction versus chromosome lagging induced by spindle inhibitors in vitro in human lymphocytes

Mutagenesis, 1997

Risk assessment from exposure to spindle inhibitors should take into account the possibility of t... more Risk assessment from exposure to spindle inhibitors should take into account the possibility of threshold concentrationresponse curves for aneuploidy induction. We analysed concentration-dependent induction of chromosome nondisjunction by well known spindle poisons (colchicine, carbendazim, mebendazole and nocodazole) and a reference clastogen, methyl methanesulphonate (MMS) in vitro in human lymphocytes; and integrated these findings with earlier results of chromosome loss in micronuclei. Chromosome non-disjunction was estimated on cytokinesis-blocked lymphocytes after simultaneous fluorescent in situ hybridization labelling with two chromosome-specific centromeric probes (chromosomes 1 and 17). The frequencies of spontaneous non-disjunction showed important inter-individual variations and were surprisingly high (7.04-15.39%). Lower concentrations of aneugens did not induce a statistically significant increase of non-disjunction frequencies over the respective control levels, whereas higher concentrations clearly induced a concentration-dependent increase in the non-disjunction frequencies with the four aneugens tested. On the contrary, even at high concentrations, MMS induced a slight increase in the frequency of non-disjunction but without being statistically significant when compared with the control frequencies. We estimated the inflection points, the first statistically significant concentrations, the last nonstatistically significant concentrations and the number of events from concentration-response curves of chromosome non-disjunction and chromosome loss. A threshold-type of concentration-response for non-disjunction is highly probable for colchicine and nocodazole. For carbendazim and mebendazole the inflection point fell above the first statistically significant concentrations. But since it is obvious from dose-response curves where the inflection point/ threshold lies, it appears that the model might be picking up some irregularities (possibly due to experimental variability in the dose-response curve at concentrations greater than the threshold). For accurate estimation of the threshold, analysis of more concentrations or more cells might be needed. Our data strongly indicate that in cultured human lymphocytes chromosome non-disjunction is a major mechanism of aneuploidy induction by spindle inhibitors and since non-disjunction occurs at lower concentration than chromosome loss, the aneuploidy threshold should be estimated on the basis of non-disjunction rather than on micronuclei frequencies (chromosome loss).