Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 183
Filtrar
1.
Artigo em Inglês | MEDLINE | ID: mdl-34596659

RESUMO

BACKGROUND: Heart failure (HF) trials have stringent in- and ex- clusion criteria, but limited data exists regarding generalisability of trials. We compared patient characteristics and outcomes between patients with HF and reduced ejection fraction (HFrEF) in trials and observational registries. METHODS AND RESULTS: Individual patient data for 16922 patients from five randomised clinical trials and 46914 patients from two HF registries were included. The registry patients were categorised into trial-eligible and non-eligible groups using the most commonly used in- and ex-clusion criteria. A total of 26104 (56%) registry patients fulfilled the eligibility criteria. Unadjusted all-cause mortality rates at one year were lowest in the trial population (7%), followed by trial-eligible patients (12%) and trial-non-eligible registry patients (26%). After adjustment for age and sex, all-cause mortality rates were similar between trial participants and trial-eligible registry patients (standardised mortality ratio (SMR) 0.97; 95% confidence interval (CI) 0.92 -1.03) but cardiovascular mortality was higher in trial participants (SMR 1.19; 1.12 -1.27). After full case-mix adjustment, the SMR for cardiovascular mortality remained higher in the trials at 1.28 (1.20- 1.37) compared to RCT-eligible registry patients. CONCLUSION: In contemporary HF registries, over half of HFrEF patients would have been eligible for trial enrolment. Crude clinical event rates were lower in the trials, but, after adjustment for case-mix, trial participants had similar rates of survival as registries. Despite this, they had about 30% higher cardiovascular mortality rates. Age and sex were the main drivers of differences in clinical outcomes between HF trials and observational HF registries.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34506972

RESUMO

BACKGROUND: Mechanism-based treatments such as bumetanide are being repurposed for autism spectrum disorder. We recently reported beneficial effects on repetitive behavioral symptoms that might be related to regulating excitation-inhibition (E/I) balance in the brain. Here, we tested the neurophysiological effects of bumetanide and the relationship to clinical outcome variability and investigated the potential for machine learning-based predictions of meaningful clinical improvement. METHODS: Using modified linear mixed models applied to intention-to-treat population, we analyzed E/I-sensitive electroencephalography (EEG) measures before and after 91 days of treatment in the double-blind, randomized, placebo-controlled Bumetanide in Autism Medication and Biomarker study. Resting-state EEG of 82 subjects out of 92 participants (7-15 years) were available. Alpha frequency band absolute and relative power, central frequency, long-range temporal correlations, and functional E/I ratio treatment effects were related to the Repetitive Behavior Scale-Revised (RBS-R) and the Social Responsiveness Scale 2 as clinical outcomes. RESULTS: We observed superior bumetanide effects on EEG, reflected in increased absolute and relative alpha power and functional E/I ratio and in decreased central frequency. Associations between EEG and clinical outcome change were restricted to subgroups with medium to high RBS-R improvement. Using machine learning, medium and high RBS-R improvement could be predicted by baseline RBS-R score and EEG measures with 80% and 92% accuracy, respectively. CONCLUSIONS: Bumetanide exerts neurophysiological effects related to clinical changes in more responsive subsets, in whom prediction of improvement was feasible through EEG and clinical measures.

3.
Neurology ; 97(11): 528-536, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34315786

RESUMO

Development of effective treatments for amyotrophic lateral sclerosis (ALS) has been hampered by disease heterogeneity, a limited understanding of underlying pathophysiology, and methodologic design challenges. We have evaluated 2 major themes in the design of pivotal, phase 3 clinical trials for ALS-(1) patient selection and (2) analytical strategy-and discussed potential solutions with the European Medicines Agency. Several design considerations were assessed using data from 5 placebo-controlled clinical trials (n = 988), 4 population-based cohorts (n = 5,100), and 2,436 placebo-allocated patients from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. The validity of each proposed design modification was confirmed by means of simulation and illustrated for a hypothetical setting. Compared to classical trial design, the proposed design modifications reduce the sample size by 30.5% and placebo exposure time by 35.4%. By making use of prognostic survival models, one creates a potential to include a larger proportion of the population and maximize generalizability. We propose a flexible design framework that naturally adapts the trial duration when inaccurate assumptions are made at the design stage, such as enrollment or survival rate. In case of futility, the follow-up time is shortened and patient exposure to ineffective treatments or placebo is minimized. For diseases such as ALS, optimizing the use of resources, widening eligibility criteria, and minimizing exposure to futile treatments and placebo is critical to the development of effective treatments. Our proposed design modifications could circumvent important pitfalls and may serve as a blueprint for future clinical trials in this population.


Assuntos
Esclerose Amiotrófica Lateral/terapia , Projetos de Pesquisa , Ensaios Clínicos como Assunto , Progressão da Doença , Humanos , Seleção de Pacientes , Fatores de Risco
4.
Stat Med ; 40(15): 3533-3559, 2021 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-33948970

RESUMO

Prediction models often yield inaccurate predictions for new individuals. Large data sets from pooled studies or electronic healthcare records may alleviate this with an increased sample size and variability in sample characteristics. However, existing strategies for prediction model development generally do not account for heterogeneity in predictor-outcome associations between different settings and populations. This limits the generalizability of developed models (even from large, combined, clustered data sets) and necessitates local revisions. We aim to develop methodology for producing prediction models that require less tailoring to different settings and populations. We adopt internal-external cross-validation to assess and reduce heterogeneity in models' predictive performance during the development. We propose a predictor selection algorithm that optimizes the (weighted) average performance while minimizing its variability across the hold-out clusters (or studies). Predictors are added iteratively until the estimated generalizability is optimized. We illustrate this by developing a model for predicting the risk of atrial fibrillation and updating an existing one for diagnosing deep vein thrombosis, using individual participant data from 20 cohorts (N = 10 873) and 11 diagnostic studies (N = 10 014), respectively. Meta-analysis of calibration and discrimination performance in each hold-out cluster shows that trade-offs between average and heterogeneity of performance occurred. Our methodology enables the assessment of heterogeneity of prediction model performance during model development in multiple or clustered data sets, thereby informing researchers on predictor selection to improve the generalizability to different settings and populations, and reduce the need for model tailoring. Our methodology has been implemented in the R package metamisc.


Assuntos
Projetos de Pesquisa , Calibragem , Humanos
5.
Artigo em Inglês | MEDLINE | ID: mdl-33527843

RESUMO

Objective: The ALSFRS-R is limited by multidimensionality, which originates from the summation of various subscales. This prevents a direct comparison between patients with identical total scores. We aim to evaluate how multidimensionality affects the performance of the ALSFRS-R in clinical trials. Methods: We simulated clinical trial data with different treatment effects for the ALSFRS-R total score and its subscales (i.e. bulbar, fine motor, gross motor and respiratory). We considered scenarios where treatment reduced the rate of ALSFRS-R subscale decline either uniformly (i.e. all subscales respond identically to treatment) or non-uniformly (i.e. subscales respond differently to treatment). Two main analytical strategies were compared: (1) analyzing only the total score or (2) utilizing a subscale-based test (i.e. alternative strategy). For each analytical strategy, we calculated the empirical power and required sample size. Results: Both strategies are valid when there is no treatment benefit and provide adequate control of type 1 error. If all subscales respond identically to treatment, using the total score is the most powerful approach. As the differences in treatment responses between subscales increase, the more the total score becomes affected. For example, to detect a 40% reduction in the bulbar rate of decline with 80% power, the total score requires 1380 patients, whereas this is 336 when using the alternative strategy. Conclusions: Ignoring the multidimensional structure of the ALSFRS-R total score could have negative consequences for ALS clinical trials. We propose determining treatment benefit on a subscale level, prior to stating whether a treatment is generally effective.


Assuntos
Esclerose Amiotrófica Lateral , Progressão da Doença , Amigos , Humanos
6.
Transl Psychiatry ; 10(1): 211, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32612118

RESUMO

The use of smartphone-based location data to quantify behavior longitudinally and passively is rapidly gaining traction in neuropsychiatric research. However, a standardized and validated preprocessing framework for deriving behavioral phenotypes from smartphone-based location data is currently lacking. Here, we present a preprocessing framework consisting of methods that are validated in the context of geospatial data. This framework aims to generate context-enriched location data by identifying stationary, non-stationary, and recurrent stationary states in movement patterns. Subsequently, this context-enriched data is used to derive a series of behavioral phenotypes that are related to movement. By using smartphone-based location data collected from 245 subjects, including patients with schizophrenia, we show that the proposed framework is effective and accurate in generating context-enriched location data. This data was subsequently used to derive behavioral readouts that were sensitive in detecting behavioral nuances related to schizophrenia and aging, such as the time spent at home and the number of unique places visited. Overall, our results indicate that the proposed framework reliably preprocesses raw smartphone-based location data in such a manner that relevant behavioral phenotypes of interest can be derived.


Assuntos
Esquizofrenia , Smartphone , Humanos , Fenótipo
7.
Malar J ; 19(1): 119, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32197619

RESUMO

BACKGROUND: Drug safety assessments in clinical trials present unique analytical challenges. Some of these include adjusting for individual follow-up time, repeated measurements of multiple outcomes and missing data among others. Furthermore, pre-specifying appropriate analysis becomes difficult as some safety endpoints are unexpected. Although existing guidelines such as CONSORT encourage thorough reporting of adverse events (AEs) in clinical trials, they provide limited details for safety data analysis. The limited guidelines may influence suboptimal analysis by failing to account for some analysis challenges above. A typical example where such challenges exist are trials of anti-malarial drugs for malaria prevention during pregnancy. Lack of proper standardized evaluation of the safety of antimalarial drugs has limited the ability to draw conclusions about safety. Therefore, a systematic review was conducted to establish the current practice in statistical analysis for preventive antimalarial drug safety in pregnancy. METHODS: The search included five databases (PubMed, Embase, Scopus, Malaria in Pregnancy Library and Cochrane Central Register of Controlled Trials) to identify original English articles reporting Phase III randomized controlled trials (RCTs) on anti-malarial drugs for malaria prevention in pregnancy published from January 2010 to July 2019. RESULTS: Eighteen trials were included in this review that collected multiple longitudinal safety outcomes including AEs. Statistical analysis and reporting of the safety outcomes in all the trials used descriptive statistics; proportions/counts (n = 18, 100%) and mean/median (n = 2, 11.1%). Results presentation included tabular (n = 16, 88.9%) and text description (n = 2, 11.1%). Univariate inferential methods were reported in most trials (n = 16, 88.9%); including Chi square/Fisher's exact test (n = 12, 66.7%), t test (n = 2, 11.1%) and Mann-Whitney/Wilcoxon test (n = 1, 5.6%). Multivariable methods, including Poisson and negative binomial were reported in few trials (n = 3, 16.7%). Assessment of a potential link between missing efficacy data and safety outcomes was not reported in any of the trials that reported efficacy missing data (n = 7, 38.9%). CONCLUSION: The review demonstrated that statistical analysis of safety data in anti-malarial drugs for malarial chemoprevention in pregnancy RCTs is inadequate. The analyses insufficiently account for multiple safety outcomes potential dependence, follow-up time and informative missing data which can compromise anti-malarial drug safety evidence development, based on the available data.


Assuntos
Antimaláricos/administração & dosagem , Quimioprevenção/estatística & dados numéricos , Malária/prevenção & controle , Complicações Infecciosas na Gravidez/prevenção & controle , Adulto , Antimaláricos/efeitos adversos , Quimioprevenção/métodos , Interpretação Estatística de Dados , Feminino , Humanos , Gravidez , Complicações Infecciosas na Gravidez/parasitologia , Ensaios Clínicos Controlados Aleatórios como Assunto
8.
PLoS One ; 15(3): e0229576, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32134933

RESUMO

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in women worldwide. The cardiovascular risk profile deteriorates after women enter menopause. By definition, women diagnosed with premature ovarian insufficiency (POI) experience menopause before 40 years of age, which may render these women even more susceptible to develop CVD later in life. However, prospective long-term follow up data of well phenotyped women with POI are scarce. In the current study we compare the CVD profile and risk of middle aged women previously diagnosed with POI, to a population based reference group matched for age and BMI. METHODS AND FINDINGS: We compared 123 women (age 49.0 (± 4.3) years) and diagnosed with POI 8.1 (IQR: 6.8-9.6) years earlier, with 123 population controls (age 49.4 (± 3.9) years). All women underwent an extensive standardized cardiovascular screening. We assessed CVD risk factors including waist circumference, BMI, blood pressure, lipid profile, pulse wave velocity (PWV), and the prevalence of diabetes mellitus, metabolic syndrome (MetS) and carotid intima media thickness (cIMT), in both women with POI and controls. We calculated the 10-year CVD Framingham Risk Score (FRS) and the American Heart Association's suggested cardiovascular health score (CHS). Waist circumference (90.0 (IQR: 83.0-98.0) versus 80.7 (IQR: 75.1-86.8), p < 0.01), waist-to-hip ratio (0.90 (IQR: 0.85-0.93) versus 0.79 (IQR: 0.75-0.83), p < 0.01), systolic blood pressure (124 (IQR 112-135) versus 120 (IQR109-131), p < 0.04) and diastolic blood pressure (81 (IQR: 76-89) versus 78 (IQR: 71-86), p < 0.01), prevalence of hypertension (45 (37%) versus 21 (17%), p < 0.01) and MetS (19 (16%) versus 4 (3%), p < 0.01) were all significantly increased in women with POI compared to healthy controls. Other risk factors, however, such as lipids, glucose levels and prevalence of diabetes were similar comparing women with POI versus controls. The arterial stiffness assessed by PWV was also similar in both populations (8.1 (IQR: 7.1-9.4) versus 7.9 (IQR: 7.1-8.4), p = 0.21). In addition, cIMT was lower in women with POI compared to controls (550 µm (500-615) versus 684 µm (618-737), p < 0.01). The calculated 10-year CVD risk was 5.9% (IQR: 3.7-10.6) versus 6.0% (IQR: 3.9-9.0) (p = 0.31) and current CHS was 6.1 (1.9) versus 6.5 (1.6) (p = 0.07), respectively in POI versus controls. CONCLUSIONS: Middle age women with POI presented with more unfavorable cardiovascular risk factors (increased waist circumference and a higher prevalence of hypertension and MetS) compared to age and BMI matched population controls. In contrast, the current study reveals a lower cIMT and similar 10-year cardiovascular disease risk and cardiovascular health score. In summary, neither signs of premature atherosclerosis nor a worse cardiovascular disease risk or health score were observed among middle age women with POI compared to population controls. Longer-term follow-up studies of women of more advanced age are warranted to establish whether women with POI are truly at increased risk of developing CVD events later in life. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02616510.


Assuntos
Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/fisiopatologia , Insuficiência Ovariana Primária/fisiopatologia , Aterosclerose/sangue , Aterosclerose/metabolismo , Aterosclerose/fisiopatologia , Pressão Sanguínea/fisiologia , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/metabolismo , Sistema Cardiovascular/metabolismo , Estudos de Casos e Controles , Diabetes Mellitus/fisiopatologia , Feminino , Glucose/metabolismo , Humanos , Hipertensão/sangue , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Lipídeos/sangue , Menopausa/sangue , Menopausa/metabolismo , Menopausa/fisiologia , Menopausa Precoce/sangue , Menopausa Precoce/metabolismo , Menopausa Precoce/fisiologia , Pessoa de Meia-Idade , Insuficiência Ovariana Primária/sangue , Insuficiência Ovariana Primária/metabolismo , Estudos Prospectivos , Análise de Onda de Pulso/métodos , Fatores de Risco , Rigidez Vascular/fisiologia , Circunferência da Cintura/fisiologia , Relação Cintura-Quadril/métodos
9.
Pharmacogenomics J ; 20(2): 220-226, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31624333

RESUMO

Genetic mutations related to amyotrophic lateral sclerosis (ALS) act through distinct pathophysiological pathways, which may lead to varying treatment responses. Here we assess the genetic interaction between C9orf72, UNC13A, and MOBP with creatine and valproic acid treatment in two clinical trials. Genotypic data was available for 309 of the 338 participants (91.4%). The UNC13A genotype affected mortality (p = 0.012), whereas C9orf72 repeat-expansion carriers exhibited a faster rate of decline in overall (p = 0.051) and bulbar functioning (p = 0.005). A dose-response pharmacogenetic interaction was identified between creatine and the A allele of the MOBP genotype (p = 0.027), suggesting a qualitative interaction in a recessive model (HR 3.96, p = 0.015). Not taking genetic information into account may mask evidence of response to treatment or be an unrecognized source of bias. Incorporating genetic data could help investigators to identify critical treatment clues in patients with ALS.


Assuntos
Esclerose Amiotrófica Lateral/genética , Proteína C9orf72/genética , Epistasia Genética/genética , Proteínas da Mielina/genética , Proteínas do Tecido Nervoso/genética , Farmacogenética/métodos , Esclerose Amiotrófica Lateral/diagnóstico , Esclerose Amiotrófica Lateral/epidemiologia , Método Duplo-Cego , Humanos , Mutação/genética , Países Baixos/epidemiologia , Testes Farmacogenômicos/métodos
10.
Res Synth Methods ; 11(2): 148-168, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31759339

RESUMO

Many randomized trials evaluate an intervention effect on time-to-event outcomes. Individual participant data (IPD) from such trials can be obtained and combined in a so-called IPD meta-analysis (IPD-MA), to summarize the overall intervention effect. We performed a narrative literature review to provide an overview of methods for conducting an IPD-MA of randomized intervention studies with a time-to-event outcome. We focused on identifying good methodological practice for modeling frailty of trial participants across trials, modeling heterogeneity of intervention effects, choosing appropriate association measures, dealing with (trial differences in) censoring and follow-up times, and addressing time-varying intervention effects and effect modification (interactions).We discuss how to achieve this using parametric and semi-parametric methods, and describe how to implement these in a one-stage or two-stage IPD-MA framework. We recommend exploring heterogeneity of the effect(s) through interaction and non-linear effects. Random effects should be applied to account for residual heterogeneity of the intervention effect. We provide further recommendations, many of which specific to IPD-MA of time-to-event data from randomized trials examining an intervention effect.We illustrate several key methods in a real IPD-MA, where IPD of 1225 participants from 5 randomized clinical trials were combined to compare the effects of Carbamazepine and Valproate on the incidence of epileptic seizures.


Assuntos
Metanálise como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Teorema de Bayes , Carbamazepina/uso terapêutico , Interpretação Estatística de Dados , Humanos , Modelos de Riscos Proporcionais , Convulsões/tratamento farmacológico , Software , Fatores de Tempo , Ácido Valproico/uso terapêutico
11.
Hum Reprod ; 35(9): 1954-1963, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31838515

RESUMO

In IVF/ICSI treatment, the FSH starting dose is often increased in predicted low responders from the belief that it improves the chance of having a baby by maximizing the number of retrieved oocytes. This intervention has been evaluated in several randomized controlled trials, and despite a slight increase in the number of oocytes-on average one to two more oocytes in the high versus standard dose group-no beneficial impact on the probability of a live birth has been demonstrated (risk difference, -0.02; 95% CI, -0.11 to 0.06). Still, many clinicians and researchers maintain a highly ingrained belief in 'the more oocytes, the better'. This is mainly based on cross-sectional studies, where the positive correlation between the number of retrieved oocytes and the probability of a live birth is interpreted as a direct causal relation. If the latter would be present, indeed, maximizing the oocyte number would benefit our patients. The current paper argues that the use of high FSH doses may not actually improve the probability of a live birth for predicted low responders undergoing IVF/ICSI treatment and exemplifies the flaws of directly using cross-sectional data to guide FSH dosing in clinical practice. Also, difficulties in the de-implementation of the increased FSH dosing strategy are discussed, which include the prioritization of intermediate outcomes (such as cycle cancellations) and the potential biases in the interpretation of study findings (such as confirmation or rescue bias).


Assuntos
Fertilização In Vitro , Injeções de Esperma Intracitoplásmicas , Estudos Transversais , Feminino , Hormônio Foliculoestimulante , Humanos , Nascido Vivo , Indução da Ovulação , Gravidez , Taxa de Gravidez
12.
Hum Reprod Update ; 26(1): 103-117, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31867675

RESUMO

BACKGROUND: Women diagnosed with polycystic ovary syndrome (PCOS) suffer from an unfavorable cardiometabolic risk profile, which is already established by child-bearing age. OBJECTIVE AND RATIONALE: The aim of this systematic review along with an individual participant data meta-analysis is to evaluate whether cardiometabolic features in the offspring (females and males aged 1-18 years) of women with PCOS (OPCOS) are less favorable compared to the offspring of healthy controls. SEARCH METHODS: PubMed, Embase and gray literature databases were searched by three authors independently (M.N.G., M.A.W and J.C.) (last updated on 1 February 2018). Relevant key terms such as 'offspring' and 'PCOS' were combined. Outcomes were age-specific standardized scores of various cardiometabolic parameters: BMI, blood pressure, glucose, insulin, lipid profile and the sum scores of various cardiometabolic features (metabolic sum score). Linear mixed models were used for analyses with standardized beta (ß) as outcome. OUTCOMES: Nine relevant observational studies could be identified, which jointly included 1367 children: OPCOS and controls, originating from the Netherlands, Chile and the USA. After excluding neonates, duplicate records and follow-up screenings, a total of 885 subjects remained. In adjusted analyses, we observed that OPCOS (n = 298) exhibited increased plasma levels of fasting insulin (ß = 0.21(95%CI: 0.01-0.41), P = 0.05), insulin-resistance (ß = 0.21(95%CI: 0.01-0.42), P = 0.04), triglycerides (ß = 0.19(95%CI: 0.02-0.36), P = 0.03) and high-density lipoprotein (HDL)-cholesterol concentrations (ß = 0.31(95%CI: 0.08-0.54), P < 0.01), but a reduced birthweight (ß = -116(95%CI: -195 to 38), P < 0.01) compared to controls (n = 587). After correction for multiple testing, however, differences in insulin and triglycerides lost their statistical significance. Interaction tests for sex revealed differences between males and females when comparing OPCOS versus controls. A higher 2-hour fasting insulin was observed among female OPCOS versus female controls (estimated difference for females (ßf) = 0.45(95%CI: 0.07 to 0.83)) compared to the estimated difference between males ((ßm) = -0.20(95%CI: -0.58 to 0.19)), with interaction-test: P = 0.03. Low-density lipoprotein-cholesterol differences in OPCOS versus controls were lower among females (ßf = -0.39(95%CI: -0.62 to 0.16)), but comparable between male OPCOS and male controls (ßm = 0.27(95%CI: -0.03 to 0.57)), with interaction-test: P < 0.01. Total cholesterol differences in OPCOS versus controls were also lower in females compared to the difference in male OPCOS and male controls (ßf = -0.31(95%CI: -0.57 to 0.06), ßm = 0.28(95%CI: -0.01 to 0.56), interaction-test: P = 0.01). The difference in HDL-cholesterol among female OPCOS versus controls (ßf = 0.53(95%CI: 0.18-0.88)) was larger compared to the estimated mean difference among OPCOS males and the male controls (ßm = 0.13(95%CI: -0.05-0.31), interaction-test: P < 0.01). Interaction test in metabolic sum score revealed a significant difference between females (OPCOS versus controls) and males (OPCOS versus controls); however, sub analyses performed in both sexes separately did not reveal a difference among females (OPCOS versus controls: ßf = -0.14(95%CI: -1.05 to 0.77)) or males (OPCOS versus controls: ßm = 0.85(95%CI: -0.10 to 1.79)), with P-value < 0.01. WIDER IMPLICATIONS: We observed subtle signs of altered cardiometabolic health in OPCOS. Therefore, the unfavorable cardiovascular profile of women with PCOS at childbearing age may-next to a genetic predisposition-influence the health of their offspring. Sensitivity analyses revealed that these differences were predominantly observed among female offspring aged between 1 and 18 years. Moreover, studies with minimal risk of bias should elucidate the influence of a PCOS diagnosis in mothers on both sexes during fetal development and subsequently during childhood.


Assuntos
Glicemia/análise , Doenças Cardiovasculares/fisiopatologia , HDL-Colesterol/sangue , Insulina/sangue , Síndrome do Ovário Policístico/fisiopatologia , Triglicerídeos/sangue , Adolescente , Índice de Massa Corporal , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Resistência à Insulina/fisiologia , Masculino , Metaboloma/fisiologia , Países Baixos
13.
AAS Open Res ; 3: 51, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33501413

RESUMO

The increase in health research in sub-Saharan Africa (SSA) has generated large amounts of data and led to a high demand for biostatisticians to analyse these data locally and quickly.  Donor-funded initiatives exist to address the dearth in statistical capacity, but few initiatives have been led by African institutions. The Sub-Saharan African Consortium for Advanced Biostatistics (SSACAB) aims to improve biostatistical capacity in Africa according to the needs identified by African institutions, through (collaborative) masters and doctoral training in biostatistics. We describe the SSACAB Consortium, which comprises 11 universities and four research institutions- supported by four European universities. SSACAB builds on existing resources to strengthen biostatistics for health research with a focus on supporting biostatisticians to become research leaders; building a critical mass of biostatisticians, and networking institutions and biostatisticians across SSA.  In 2015 only four institutions had established Masters programmes in biostatistics and SSACAB supported the remaining institutions to develop Masters programmes. In 2019 the University of the Witwatersrand became the first African institution to gain Royal Statistical Society accreditation for a Biostatistics MSc programme. A total of 150 fellows have been awarded scholarships to date of which 123 are Masters fellowships (41 female) of which with 58 have already graduated. Graduates have been employed in African academic (19) and research (15) institutions and 10 have enrolled for PhD studies. A total of 27 (10 female) PhD fellowships have been awarded; 4 of them are due to graduate by 2020. To date, SSACAB Masters and PhD students have published 17 and 31 peer-reviewed articles, respectively. SSACAB has also facilitated well-attended conferences, face-to-face and online short courses. Pooling the limited biostatistics resources in SSA, and combining with co-funding from external partners is an effective strategy for the development and teaching of advanced biostatistics methods, supervision and mentoring of PhD candidates.

14.
ERJ Open Res ; 5(4)2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31687368

RESUMO

Our study presents findings on a previously developed standard set of clinical outcome data for pulmonary sarcoidosis patients. We aimed to assess whether changes in outcome varied between the different centres and to evaluate the feasibility of collecting the standard set retrospectively. This retrospective observational comparative benchmark study included six interstitial lung disease expert centres based in the Netherlands, Belgium, the UK and the USA. The standard set of outcome measures included 1) mortality, 2) changes in pulmonary function (forced vital capacity (FVC), forced expiratory volume in 1 s, diffusing capacity of the lung for carbon monoxide), 3) soluble interleukin-2 receptor (sIL-2R) change, 4) weight changes, 5) quality-of-life (QoL) measures, 6) osteoporosis and 7) clinical outcome status (COS). Data collection was considered feasible if the data were collected in ≥80% of all patients. 509 patients were included in the retrospective cohort. In total six patients died, with a mean survival of 38±23.4 months after the diagnosis. Centres varied in mean baseline FVC, ranging from 110 (95% CI 92-124)% predicted to 99 (95% CI 97-123)% pred. Mean baseline body mass index (BMI) of patients in the different centres varied between 27 (95% CI 23.6-29.4) kg·m-2 and 31.8 (95% CI 28.1-35.6) kg·m-2. 310 (60.9%) patients were still on systemic therapy 2 years after the diagnosis. It was feasible to measure mortality, changes in pulmonary function, weight changes and COS. It is not (yet) feasible to retrospectively collect sIL-2R, osteoporosis and QoL data internationally. This study shows that data collection for the standard set of outcome measures for pulmonary sarcoidosis was feasible for four out of seven outcome measures. Trends in pulmonary function and BMI were similar for different hospitals when comparing different practices.

15.
J Neurol Neurosurg Psychiatry ; 90(12): 1331-1337, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31292200

RESUMO

BACKGROUND: Funding and resources for low prevalent neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) are limited, and optimising their use is vital for efficient drug development. In this study, we review the design assumptions for pivotal ALS clinical trials with time-to-event endpoints and provide optimised settings for future trials. METHODS: We extracted design settings from 13 completed placebo-controlled trials. Optimal assumptions were estimated using parametric survival models in individual participant data (n=4991). Designs were compared in terms of sample size, trial duration, drug use and costs. RESULTS: Previous trials overestimated the hazard rate by 18.9% (95% CI 3.4% to 34.5%, p=0.021). The median expected HR was 0.56 (range 0.33-0.66). Additionally, we found evidence for an increasing mean hazard rate over time (Weibull shape parameter of 2.03, 95% CI 1.93 to 2.15, p<0.001), which affects the design and planning of future clinical trials. Incorporating accrual time and assuming an increasing hazard rate at the design stage reduced sample size by 33.2% (95% CI 27.9 to 39.4), trial duration by 17.4% (95% CI 11.6 to 23.3), drug use by 14.3% (95% CI 9.6 to 19.0) and follow-up costs by 21.2% (95% CI 15.6 to 26.8). CONCLUSIONS: Implementing distributional knowledge and incorporating accrual at the design stage could achieve large gains in the efficiency of ALS clinical trials with time-to-event endpoints. We provide an open-source platform that helps investigators to make more accurate sample size calculations and optimise the use of their available resources.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Ensaios Clínicos como Assunto/métodos , Determinação de Ponto Final/métodos , Projetos de Pesquisa , Adulto , Feminino , Humanos , Masculino , Qualidade de Vida , Riluzol/uso terapêutico
16.
Artigo em Inglês | MEDLINE | ID: mdl-31271047

RESUMO

Objective: Spirometry is commonly used as screening tool for respiratory insufficiency in neuromuscular diseases. Despite the well-known effects of reference standards on spirometric outcomes, its standardization is overlooked in current guidelines. We aim to illustrate the effect of spirometric reference values on prognostication, medical decision-making, and trial eligibility in the applied setting of amyotrophic lateral sclerosis (ALS). Methods: We selected 4,651 patients with 32,022 FVC measurements from the PRO-ACT dataset. The FVC estimates were standardized according to five reference standards: Knudson '76, Knudson '83, ECSC, NHANES III, and GLI-2012. (Generalized) linear mixed-effects and Cox proportional hazard models were used to evaluate longitudinal patterns and time-to-event outcomes. Results: The mean population %predicted FVC varied between 78.5% (95% CI 78.0-79.1) and 88.5% (95% CI 87.9-89.1). The unstandardized liters provided the worst fit on the survival data (AIC 20573, c-index 0.760), whereas the GLI provided the best fit (AIC 20374, c-index 0.780, p < 0.001). The mean population rate of decline in %predicted FVC could vary as much as 11.4% between reference standards. The median time-to-50% predicted FVC differed by 2.9 months between recent (14.5 months, 95% CI 14.4-16.1) and early reference standards (17.4 months, 95% CI 16.1-18.2). Conclusion: Independent of technique, device, or evaluator, spirometric reference values affect the utility of spirometry in ALS. Standardization of reference values is of the utmost importance to optimize clinical decision-making, improve prognostication, enhance between-center comparison and unify patient selection for clinical trials.


Assuntos
Esclerose Amiotrófica Lateral , Seleção de Pacientes , Esclerose Amiotrófica Lateral/complicações , Esclerose Amiotrófica Lateral/diagnóstico , Esclerose Amiotrófica Lateral/terapia , Feminino , Humanos , Masculino , Inquéritos Nutricionais , Valores de Referência , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/fisiopatologia , Espirometria/métodos , Capacidade Vital/fisiologia
17.
J Neurol ; 266(10): 2387-2395, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31187191

RESUMO

BACKGROUND: The extensive heterogeneity between patients with amyotrophic lateral sclerosis (ALS) complicates the quantification of disease progression. In this study, we determine the value of remote, accelerometer-based monitoring of physical activity in patients with ALS. METHODS: This longitudinal cohort study was conducted in a home-based setting; all study materials were sent by mail. Patients wore the ActiGraph during waking hours for 7 days every 2-3 months and provided information regarding their daily functioning (ALSFRS-R). We defined four accelerometer-based endpoints that either reflect the average daily activity or quantify the patient's physical capacity. RESULTS: A total of 42 patients participated; the total valid monitoring period was 9288 h with a 93.0% adherence rate. At baseline, patients were active 27.9% (range 11.6-52.4%) of their time; this declined by 0.64% (95% 0.43-0.86, p < 0.001) per month. Accelerometer-based endpoints were strongly associated with the ALSFRS-R (r 0.78, 95% CI 0.63-0.92, p < 0.001), but showed less variability over time than the ALSFRS-R (coefficient of variation 0.64-0.81 vs. 1.06, respectively). Accelerometer-based endpoints could reduce sample size by 30.3% for 12-month trials and 44.6% for 18-month trials; for trials lasting less than 9 months, the ALSFRS-R resulted in smaller sample sizes. CONCLUSION: Accelerometry is an objective method for quantifying disease progression, which could obtain real-world insights in the patient's physical functioning and may personalize the delivery of care. In addition, remote monitoring provides patients with the opportunity to participate in clinical trials from home, paving the way to a patient-centric clinical trial model.


Assuntos
Acelerometria/normas , Esclerose Amiotrófica Lateral/diagnóstico , Esclerose Amiotrófica Lateral/fisiopatologia , Progressão da Doença , Exercício Físico , Monitorização Ambulatorial/normas , Idoso , Exercício Físico/fisiologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
18.
Acta Obstet Gynecol Scand ; 98(10): 1332-1340, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31127607

RESUMO

INTRODUCTION: The OPTIMIST trial revealed that for women starting in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment, no substantial differences exist in first cycle and cumulative live birth rates between an antral follicle count (AFC)-based individualized follicle-stimulating hormone (FSH) dose and a standard dose. Female age and body weight have been suggested to cause heterogeneity in the effect of FSH dose individualization. The objective of the current study is to evaluate whether these patient characteristics modify the effect of AFC-based individualized FSH dosing in IVF/ICSI treatment. MATERIAL AND METHODS: A secondary data-analysis of the OPTIMIST trial. Women initiating IVF/ICSI treatment were classified as predicted poor (AFC 0-7), suboptimal (AFC 8-10) or hyper responders (AFC >15), and randomly allocated to a standard FSH dose (150 IU/d) or an individualized FSH dose (450, 225 or 100 IU/d for predicted poor, suboptimal and hyper responders, respectively). In each predicted response category, logistic regression models with interaction terms were used to evaluate the presence of effect modification. The first cycle was analyzed, and the primary outcomes were first complete cycle live birth rate (including fresh plus frozen-thawed embryo transfers) and ovarian hyperstimulation syndrome (OHSS) risks. RESULTS: No effect modification was revealed in the predicted poor (n = 234) and suboptimal (n = 277) responders. In the predicted hyper responders (n = 521), the effect of the individualized FSH dose on the first cycle live birth rate was modified by female age (P = 0.02) and the effect on OHSS risks was modified by body weight (P = 0.02). A dose reduction from 150 to 100 IU/d generally decreased the OHSS risks in predicted hyper responders, but also reduced the chance of a live birth in young women, and had no beneficial impact on OHSS risks in women with a relatively low body weight. CONCLUSIONS: In women with a predicted hyper response undergoing IVF/ICSI treatment, female age and body weight seem to modify the effect of FSH dose individualization. Although a reduced FSH starting dose generally decreases the OHSS risks, it may also reduce the chance of a live birth, specifically for young women. Future studies could consider these findings when investigating the optimal approach to reduce OHSS risks while maintaining the probability of a live birth for predicted hyper responders in IVF/ICSI treatment.


Assuntos
Peso Corporal , Fertilização In Vitro , Hormônio Foliculoestimulante/administração & dosagem , Injeções de Esperma Intracitoplásmicas , Adulto , Fatores Etários , Feminino , Humanos , Nascido Vivo , Países Baixos , Estudos Prospectivos
19.
Hum Reprod ; 34(6): 1030-1041, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31125412

RESUMO

STUDY QUESTION: Do cumulative live birth rates (CLBRs) over multiple IVF/ICSI cycles confirm the low prognosis in women stratified according to the POSEIDON criteria? SUMMARY ANSWER: The CLBR of low-prognosis women is ~56% over 18 months of IVF/ICSI treatment and varies between the POSEIDON groups, which is primarily attributable to the impact of female age. WHAT IS KNOWN ALREADY: The POSEIDON group recently proposed a new stratification for low-prognosis women in IVF/ICSI treatment, with the aim to define more homogenous populations for clinical trials and stimulate a patient-tailored therapeutic approach. These new criteria combine qualitative and quantitative parameters to create four groups of low-prognosis women with supposedly similar biologic characteristics. STUDY DESIGN, SIZE, DURATION: This study analyzed the data of a Dutch multicenter observational cohort study including 551 low-prognosis women, aged <44 years, who initiated IVF/ICSI treatment between 2011 and 2014 and were treated with a fixed FSH dose of 150 IU/day in the first treatment cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: Low-prognosis women were categorized into one of the POSEIDON groups based on their age (younger or older than 35 years), anti-Müllerian hormone (AMH) level (above or below 0.96 ng/ml), and the ovarian response (poor or suboptimal) in their first cycle of standard stimulation. The primary outcome was the CLBR over multiple complete IVF/ICSI cycles, including all subsequent fresh and frozen-thawed embryo transfers, within 18 months of treatment. Cumulative incidence curves were obtained using an optimistic and a conservative analytic approach. MAIN RESULTS AND THE ROLE OF CHANCE: The CLBR of the low-prognosis women was on average ~56% over 18 months of IVF/ICSI treatment. Younger unexpected poor (n = 38) and suboptimal (n = 179) responders had a CLBR of ~65% and ~68%, respectively, and younger expected poor responders (n = 65) had a CLBR of ~59%. The CLBR of older unexpected poor (n = 41) and suboptimal responders (n = 102) was ~42% and ~54%, respectively, and of older expected poor responders (n = 126) ~39%. For comparison, the CLBR of younger (n = 164) and older (n = 78) normal responders with an adequate ovarian reserve was ~72% and ~58% over 18 months of treatment, respectively. No large differences were observed in the number of fresh treatment cycles between the POSEIDON groups, with an average of two fresh cycles per woman within 18 months of follow-up. LIMITATIONS, REASONS FOR CAUTION: Small numbers in some (sub)groups reduced the precision of the estimates. However, our findings provide the first relevant indication of the CLBR of low-prognosis women in the POSEIDON groups. Small FSH dose adjustments between cycles were allowed, inducing therapeutic disparity. Yet, this is in accordance with current daily practice and increases the generalizability of our findings. WIDER IMPLICATIONS OF THE FINDINGS: The CLBRs vary between the POSEIDON groups. This heterogeneity is primarily determined by a woman's age, reflecting the importance of oocyte quality. In younger women, current IVF/ICSI treatment reaches relatively high CLBR over multiple complete cycles, despite reduced quantitative parameters. In older women, the CLBR remains relatively low over multiple complete cycles, due to the co-occurring decline in quantitative and qualitative parameters. As no effective interventions exist to counteract this decline, clinical management currently relies on proper counselling. STUDY FUNDING/COMPETING INTEREST(S): No external funds were obtained for this study. J.A.L. is supported by a Research Fellowship grant and received an unrestricted personal grant from Merck BV. S.C.O., T.C.v.T., and H.L.T. received an unrestricted personal grant from Merck BV. C.B.L. received research grants from Merck, Ferring, and Guerbet. K.F. received unrestricted research grants from Merck Serono, Ferring, and GoodLife. She also received fees for lectures and consultancy from Ferring and GoodLife. A.H. declares that the Department of Obstetrics and Gynaecology, University Medical Centre Groningen received an unrestricted research grant from Ferring Pharmaceuticals BV, the Netherlands. J.S.E.L. has received unrestricted research grants from Ferring, Zon-MW, and The Dutch Heart Association. He also received travel grants and consultancy fees from Danone, Euroscreen, Ferring, AnshLabs, and Titus Healthcare. B.W.J.M. is supported by an National Health and Medical Research Council Practitioner Fellowship (GNT1082548) and reports consultancy work for ObsEva, Merck, and Guerbet. He also received a research grant from Merck BV and travel support from Guerbet. F.J.M.B. received monetary compensation as a member of the external advisory board for Merck Serono (the Netherlands) and Ferring Pharmaceuticals BV (the Netherlands) for advisory work for Gedeon Richter (Belgium) and Roche Diagnostics on automated AMH assay development, and for a research cooperation with Ansh Labs (USA). All other authors have nothing to declare. TRIAL REGISTRATION NUMBER: Not applicable.


Assuntos
Coeficiente de Natalidade , Transferência Embrionária/estatística & dados numéricos , Infertilidade Feminina/terapia , Nascido Vivo , Injeções de Esperma Intracitoplásmicas/estatística & dados numéricos , Adulto , Fatores Etários , Hormônio Antimülleriano/sangue , Feminino , Humanos , Infertilidade Feminina/sangue , Infertilidade Feminina/diagnóstico , Infertilidade Feminina/fisiopatologia , Países Baixos/epidemiologia , Reserva Ovariana/fisiologia , Gravidez , Prognóstico , Fatores de Tempo
20.
Clin Endocrinol (Oxf) ; 91(2): 314-322, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31049984

RESUMO

OBJECTIVE: Women with premature ovarian insufficiency (POI) enter menopause before age 40. Early menopause was associated with increased risk for coronary artery disease (CAD), death from cardiovascular disease and all-cause mortality. We compared the prevalence of CAD between middle-aged women on average 10 years following the initial POI diagnosis, with a population-based cohort. DESIGN: Cross-sectional case-control study. PARTICIPANTS: Women from two Dutch University Medical Centers above 45 years of age previously diagnosed with POI (n = 98) were selected and compared with age- and race-matched controls from the Multi-Ethnic Study of Atherosclerosis (MESA). MEASUREMENTS: The primary outcome was detectable coronary artery calcium (CAC) determined by coronary computed tomography (CCT). RESULTS: Women with POI had significantly higher blood pressure, cholesterol and glucose, despite lower BMI compared to controls. Similar proportions of detectable CAC (CAC score >0 Agatston Units) were observed in women with POI and controls (POI n = 16 (16%), controls n = 52 (18%), P = 0.40 and Padj  = 0.93). In women with POI separately, we were not able to identify associations between CVD risk factors and CAC. The following CVD risk factors in controls were positively associated with CAC: age, diabetes mellitus, hypertension and LDL cholesterol. HRT use was negatively associated with CAC in controls. CONCLUSIONS: The presence of CAC did not differ significantly in women with POI around 50 years of age, compared to an age- and race-matched control group. We observe no increased calcified coronary disease in POI patients, despite the presence of unfavourable cardiovascular risk factors in these women.


Assuntos
Calcinose/patologia , Vasos Coronários/patologia , Insuficiência Ovariana Primária/complicações , Idoso , Calcinose/complicações , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...