Inhibition of microRNA-92a prevents endothelial dysfunction and atherosclerosis in mice.

RATIONALE FOR STUDY: MicroRNAs (miRNAs) are small noncoding RNAs that regulate protein expression at post-transcriptional level. We hypothesized that a specific pool of endothelial miRNAs could be selectively regulated by flow conditions and inflammatory signals, and as such be involved in the development of atherosclerosis. OBJECTIVE: To identify miRNAs, called atheromiRs, which are selectively regulated by shear stress and oxidized low-density lipoproteins (oxLDL), and to determine their role in atherogenesis. METHODS AND RESULTS: Large-scale miRNA profiling in HUVECs identified miR-92a as an atheromiR candidate, whose expression is preferentially upregulated by the combination of low shear stress (SS) and atherogenic oxLDL. Ex vivo analysis of atheroprone and atheroprotected areas of mouse arteries and human atherosclerotic plaques demonstrated the preferential expression of miR-92a in atheroprone low SS regions. In Ldlr(-/-) mice, miR-92a expression was markedly enhanced by hypercholesterolemia, in particular in atheroprone areas of the aorta. Assessment of endothelial inflammation in gain- and loss-of-function experiments targeting miR-92a expression revealed that miR-92a regulated endothelial cell activation by oxLDL, more specifically under low SS conditions, which was associated with modulation of Kruppel-like factor 2 (KLF2), Kruppel-like factor 4 (KLF4), and suppressor of cytokine signaling 5. miR-92a expression was regulated by signal transducer and activator of transcription 3 in SS- and oxLDL-dependent manner. Furthermore, specific in vivo blockade of miR-92a expression in Ldlr(-/-) mice reduced endothelial inflammation and altered the development of atherosclerosis, decreasing plaque size and promoting a more stable lesion phenotype. CONCLUSIONS: Upregulation of miR-92a by oxLDL in atheroprone areas promotes endothelial activation and the development of atherosclerotic lesions. Therefore, miR-92a antagomir seems as a new atheroprotective therapeutic strategy.

Confirmatory Factor Analysis Compared with Principal Component Analysis to Derive Dietary Patterns: A Longitudinal Study in Adult Women.

BACKGROUND: Principal component analysis (PCA) has been used extensively to derive dietary patterns. We proposed to use confirmatory factor analysis (CFA) in the same context as PCA--as a one-step approach--to derive dietary patterns. OBJECTIVES: The first aim of this study was methodologic and was to compare dietary patterns derived with the use of PCA and CFA, used as equivalent one-step approaches. The second aim of this study was to study these patterns in association with individual characteristics and new adult-onset asthma. METHODS: We included 30,589 French women from the E3N (epidemiologic prospective cohort study of women from the MGEN national insurance plan) with 1177 reported cases of adult-onset asthma between 1993 and 2005. PCA and CFA were used in the same context, on 27 food groups, to derive dietary patterns. Associations between dietary patterns and adult-onset asthma were assessed by Cox proportional hazards models. RESULTS: Whether we used PCA or CFA, 3 similar factors were found and labeled "Prudent," "Western," and "Aperitif." Correlations between patterns derived with the use of PCA and CFA were high. For the "Prudent" and "Aperitif" patterns, we observed comparable patterns in terms of associations with food groups, individual characteristics, and the onset of asthma. For the "Western" patterns, the one derived with the use of CFA was more related to an unhealthy diet than the one derived with the use of PCA, with higher correlations with the food groups "processed meat" (0.73 vs. 0.51) and "dough and pastry" (0.63 vs. 0.40), and negative associations with physical activity and with having parents who were farmers. Regarding associations with adult-onset asthma, a significant positive association was observed for the "Western" pattern derived with the use of CFA [multivariate RR for highest vs. lowest quintile: 1.30 (1.02, 1.67), P-trend: 0.03], whereas no association was reported when using PCA [RR: 1.14 (0.89, 1.47), P-trend: 0.40]. CONCLUSION: Although quite similar dietary patterns were derived with the use of PCA and CFA, this study supports the alternative use of CFA to PCA for the identification of dietary patterns in epidemiologic studies.

Dose-dependent beneficial effects of citrulline supplementation in short bowel syndrome in rats.

OBJECTIVES: Supplementing diet with citrulline has proved an efficient means of preserving nitrogen balance and improving nutritional status after massive intestinal resection. The aim of this study was to model the action of citrulline in gut-resected rats using a dose-ranging study focused on skeletal muscle nitrogen homeostasis. METHODS: Forty-six rats were randomly assigned to one of the following groups: citrulline 0.5 g·kg·d-1 (n = 9), citrulline 1 g·kg·d-1 (n = 7), citrulline 2.5 g·kg·d-1 (n = 8), citrulline 5 g·kg·d-1 (n = 8), control (n = 6), and sham (n = 8). The sham group underwent transection and the other groups underwent resection of 80% of the small intestine. All rats were then fed enteral nutrition (EN; all diets were isocaloric and isonitrogenous). After 10 d, the rats were sacrificed to measure and analyze animal weight; duodenum, jejunum, and ileum weight; and muscle trophicity. Protein fractional synthesis rate (FSR) and mammalian target of rapamycin complex (mTORC)1 activation were measured in the tibialis muscle. RESULTS: There was a significant dose-dependent association between rat weight and citrulline dose up to 2.5 g·kg·d-1 (P = 0.004). There was a significant improvement in tibialis weight correlated to plasma citrulline. Net protein FSR in the tibialis tended to be greater after resection and tended to return to baseline after citrulline supplementation. Citrulline supplementation significantly decreased the activated phosphorylated forms of S6 K1 (P = 0.003) and S6 RP (P = 0.003), with a significant positive association between myofibrillar FSR and activation of S6 K1 (r = 0.614; P = 0.02) and S6 RP (r = 0.601; P = 0.023). Jejunum weight was significantly positively correlated with plasma citrulline (r = 0.319; P = 0.0345). CONCLUSION: Citrulline promotes body weight gain, preserves muscle trophicity, and enhances intestinal adaptation in a dose-dependent manner in a model of resected rats.

A big-data approach to producing descriptive anthropometric references: a feasibility and validation study of paediatric growth charts.

BACKGROUND: Both national and WHO growth charts have been found to be poorly calibrated with the physical growth of children in many countries. We aimed to generate new national growth charts for French children in the context of huge datasets of physical growth measurements routinely collected by office-based health practitioners. METHODS: We recruited 32 randomly sampled primary care paediatricians and ten volunteer general practitioners from across the French metropolitan territory who used the same electronic medical records software, from which we extracted all physical growth data for the paediatric patients, with anonymisation. We included measurements from all children born from Jan 1, 1990, and aged 1 month to 18 years by Feb 8, 2018, with birthweight greater than 2500 g, to which an automated process of data cleaning developed to detect and delete measurement or transcription errors was applied. Growth charts for weight and height were derived by using generalised additive models for location, scale, and shape with the Box-Cox power exponential distribution. We compared the new charts to WHO growth charts and existing French national growth charts, and validated our charts using growth data from recent national cross-sectional surveys. FINDINGS: After data cleaning, we included 1 458 468 height and 1 690 340 weight measurements from 238 102 children. When compared with the existing French national and WHO growth charts, all height SD and weight percentile curves for the new growth charts were distinctly above those for the existing French national growth charts, as early as age 1 month, with an average difference of -0·75 SD for height and -0·50 SD for weight for both sexes. Comparison with national cross-sectional surveys showed satisfactory calibration, with generally good fit for children aged 5-6 years and 10-11 years in height and weight and small differences at age 14-15 years. INTERPRETATION: We successfully produced calibrated paediatric growth charts by using a novel big-data approach applied to data routinely collected in clinical practice that could be used in many fields other than anthropometry. FUNDING: The French Ministry of Health; Laboratoires Guigoz-General Pediatrics section of the French Society of Pediatrics-Pediatric Epidemiological Research Group; and the French Association for Ambulatory Pediatrics.

Measurement of sunscreen immune protection factors in humans: a consensus paper.

It is increasingly accepted that sunscreens should protect against ultraviolet radiation (UVR)-induced immunosuppression, with an index of protection that can be compared with the sun protection factor (SPF). Five groups of immunoprotection researchers met to discuss the status of immune protection factor (IPF) evaluation in human skin in vivo. Current methods rely on a suncreen's inhibition of UVR-induced local suppression of the contact hypersensitivity (CHS) response or the delayed-type hypersensitivity (DTH) response, using either the induction or the elicitation arms of these responses. The induction arm of the CHS response has the advantage of being sensitive to a single sub-erythemal exposure of solar-simulating radiation (SSR) that allows a direct comparison with the SPF. This approach, which necessitates sensitization, requires a large number of volunteers and is too labor intensive and time consuming to become a routine method. The elicitation arm of the CHS or DTH responses exploits prior sensitization to contact or recall antigens and has the advantage of being possible to apply on small groups of volunteers. Some current protocols, however, require repeat SSR exposures, which invalidates a direct comparison with SPF that is based on a single exposure. There is a need for a new simpler method of IPF that will have to be validated against existing models.

Familial correlations and inter-relationships of four asthma-associated quantitative phenotypes in 320 French EGEA families ascertained through asthmatic probands.

Asthma is a complex disease, associated with biological and physiological phenotypes including immunoglobulin E (IgE) levels, sum of positive skin prick tests to allergens (SPTQ), eosinophil counts (EOS) and percent predicted forced expiratory volume in 1 s (%FEV1). We investigated the patterns of familial correlations and the inter-relationships of these four quantitative phenotypes, using the general class D regressive model, in 320 French EGEA nuclear families ascertained through 204 offspring (set A) and 116 parents (set B). Familial correlations of IgE and SPTQ were consistent with a model including no spouse correlation and equal parent-offspring and sib-sib correlations (rhoPO = rhoSS = 0.25 for IgE and 0.15 for SPTQ), this model being compatible with an additive polygenic model in the whole sample and the two family subsets A and B. Different patterns of familial correlations of EOS and %FEV1 were observed in these two sets. In set A, the best fitting model included no spouse correlation and equality of parent-offspring and sib-sib correlations (rhoPO = rhoSS = 0.14 for EOS and 0.23 for %FEV1). In set B, EOS had only a significant rhoSS of 0.28, while %FEV1 had significant rhoMO of 0.28 and rhoSS of 0.16. Analysis of shared familial determinants between these phenotypes indicated an overlap of at most 30% in rhoFO for IgE and SPTQ and in both rhoFO and rhoMO for IgE and EOS, while determinants of %FEV1 and atopy-related phenotypes appear distinct. These results may have implications for further linkage and association studies with genetic markers.

MDR-1 C3435T polymorphism influences cyclosporine a dose requirement in liver-transplant recipients.

BACKGROUND: Cyclosporine A (CsA) is characterized by high interindividual variations in oral bioavailability and a narrow therapeutic index. CsA is a substrate for P-glycoprotein, a member of the ABC transporter family encoded by the multiple drug-resistant gene MDR1. METHODS: Because MDR1 gene exon 26 C3435T polymorphism influences intestinal P-glycoprotein expression, we investigated whether this polymorphism was correlated with variation in CsA dose requirement and concentration/dose ratio in 44 liver-transplant recipients during 1 month after transplantation. CsA concentration was measured 2 hours after administration (C2), according to international recommendations. RESULTS: The MDR-1 wild-type genotype (3435CC) was observed in 15 patients (34%), whereas 21 (48%) patients were heterozygous (3435CT), and 8 (18%) patients were homozygous for the mutation (3435TT). There was no significant difference between the three groups regarding corticosteroids treatment or renal function during this period. One to 3 days after liver transplantation, when every patient received a similar CsA weight-adjusted dose, the concentration/dose ratio was correlated with exon 26 single nucleotide polymorphism and was significantly higher in subjects homozygous for the mutation (P=0.012). This was confirmed 1 month after transplantation (P=0.049), when the dose was adjusted to maintain the C2 target level of 1,000 microg/L and we observed that TT patients required approximately 50% lower weight-adjusted CsA dose than wild-type patients (P=0,033). CONCLUSIONS: These findings demonstrate that the MDR1 exon 26 C3435T polymorphism is a major determinant of CsA concentration/dose ratio in liver-transplant recipients and is predictive of the dose of CsA to be administered to achieve the target C(2) concentration.

Complex dispersions of multilamellar vesicles: a promising new carrier for controlled release and protection of encapsulated molecules.

Multilamellar vesicles called Spherulites have recently been discovered and are being developed for encapsulation applications. In this study, we present new systems of Spherulites called complex dispersions. These are prepared by dispersing Spherulites within an oily medium, and then emulsifying this oily dispersion of Spherulites within an aqueous solvent. The ability of complex dispersions to reduce the release of encapsulated ions under variable osmotic dilutions was evaluated and compared with Spherulites directly dispersible in an aqueous medium, and with multiple emulsions. An advantage of complex dispersions over Spherulites is to present an additional oily barrier. Indeed, this barrier retarded the release of encapsulated ions. Complex dispersions also proved to be less sensitive to osmotic pressure than multiple emulsions. It appeared that the dilution of a complex dispersion formulated with no external aqueous phase containing a hydrophilic surfactant provided the slowest release of encapsulated ions. Furthermore, this formulation maintained a difference of pH between the internal and external aqueous phases for a few hours. In conclusion, these new systems of Spherulites known as complex dispersions show great potential for pharmaceutical applications such as controlled release and protection of encapsulated substances.

Assessment of dietary patterns in nutritional epidemiology: principal component analysis compared with confirmatory factor analysis.

BACKGROUND: In the field of nutritional epidemiology, principal component analysis (PCA) has been used to derive patterns, but the robustness of interpretation might be an issue when the sample size is small. The authors proposed the alternative use of confirmatory factor analysis (CFA) to define such patterns. OBJECTIVE: The aim was to compare dietary patterns derived through PCA and CFA used as equivalent approaches in terms of stability and relevance. DESIGN: PCA and CFA were performed in 2 different studies: the Epidemiological Study on the Genetics and Environment of Asthma 2-France (EGEA2-France; n = 1236) and the Phenotype and Course of Chronic Obstructive Pulmonary Disease study-Spain (n = 274). To check for stability, PCA and CFA were also performed in 2 subsamples from the EGEA2 study (n = 618 and 309). Statistical proprieties were evaluated by 1000 bootstrapped random sets of observations for each of the 4 subsamples. For each random set of observations, the distribution of the factor loading for each pattern was obtained and represented by using box-plots. To check for relevance, partial correlations between different nutrients and the different patterns derived by either PCA or CFA were calculated. RESULTS: With the use of CFA, 2 consistent dietary patterns were derived in each subsample (the Prudent and the Western patterns), whereas dietary factors were less interpretable with the use of PCA (smaller median of factor loadings and higher dispersion), especially for the smallest subsample. Higher correlations were reported among total fiber, vitamins, minerals, and total lipids with patterns derived by using CFA than with patterns derived by using PCA. CONCLUSION: The current study shows that CFA may be a useful alternative to PCA in epidemiologic studies, especially when the sample size is small.

Parental body size and early weight and height growth velocities in their offspring.

BACKGROUND: Whereas weight or height at a given age are the results of the cumulative growth experience, growth velocities allows the study of factors affecting growth at given ages. AIM: To study the relationships between parental height and body mass index (BMI) and offspring's height and weight growth during infancy and childhood. STUDY DESIGN: From the FLVSII population-based study, 235 parent-child trios belonging to 162 families examined in 1999. OUTCOME MEASURES: From medical records and previous FLVS examinations, child's height and weight history were reconstructed. Weight and height growth velocities from birth to seven years were estimated from a modelling of individual growth curve and correlated with parent's body size in 1999. RESULTS: Ponderal index and length at birth were significantly associated with maternal but not paternal BMI and height. In the first six months, height growth velocity was significantly associated with maternal stature (at three months: 0.12+/-0.05 and 0.02+/-0.05 cm/month for a 10 cm difference in maternal and paternal height respectively) and weight growth velocity with paternal BMI (at three months: 5.7+/-2.8 and 1.9+/-2.3g/month for a difference of 1 kg/m(2) in paternal and maternal BMI respectively). Between two and five years, height growth velocity was more significantly associated with paternal height whereas weight growth velocity was more closely associated with maternal BMI. CONCLUSIONS: Early childhood growth is characterised by alternate periods associated specifically with maternal or paternal BMI and height. This novel finding should trigger the search for specific genetic, epigenetic or environmentally shared factors from the mothers and fathers.

Passive and active smoking and exhaled nitric oxide levels according to asthma and atopy in adults.

BACKGROUND: No data are available regarding the utility of fractional exhaled nitric oxide (FeNO) level in guiding therapy in smoking asthmatic patients. Identification of the effect of smoking in a large sample is needed. OBJECTIVE: To study the association between smoking and FeNO level according to current asthma and atopy status in adults from the French EGEA (Epidemiological study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy). METHODS: Levels of FeNO were measured at 50 mL/s in 654 adults (268 asthmatic participants). Active smoking and environmental tobacco smoke (ETS) exposure at home, at work, and during leisure activities were recorded. Participants were categorized as having no exposure to ETS, mild exposure (ETS <2 h/d), and noticeable exposure (ETS > or = 2 h/d). Multivariate analyses were performed, with adjustment for age, sex, height, and center. RESULTS: Mean adjusted FeNO values increased with asthma (15.1 vs 19.5 ppb), atopy (14.2 vs 18.9 ppb), and eosinophilia (15.8 vs 24.8 ppb) (P < .001 for all). Mean FeNO levels decreased with smoking (18.4, 17.5, and 14.5 ppb in nonsmokers, ex-smokers, and current smokers, respectively; P for trend = .001). The association with smoking was observed in nonasthmatic and asthmatic participants, especially in atopic asthmatic participants. Multivariate analyses showed that ETS exposure of at least 2 h/d and active smoking were negatively and significantly associated with FeNO levels independent of age, sex, height, and center in nonasthmatic participants (mean [SE], -0.13 [0.06], P = .03 and -0.10 [0.03], P < .001) and in asthmatic participants (mean [SE], -0.18 [0.07], P = .01 and -0.14 [0.04], P = .02). CONCLUSIONS: Active and passive smoking decreased FeNO levels in adults. Careful consideration of asthma, atopy, and active and passive smoking are needed to interpret FeNO values.

Antitumor vectorized oligonucleotides in a model of ewing sarcoma: unexpected role of nanoparticles.

Oligonucleotides (ONs) such as antisense oligonucleotides (AS-ON) and siRNAs are used as experimental tools to study gene function and are currently being tested in clinical trials for use as therapeutic anticancer agents. However, their therapeutic use has been limited by their low physiological stability and their slow cellular uptake. The systemic delivery of sequence-specific AS-ON targeting the EWS/FLI1 gene product by a targeted, nonviral delivery system dramatically inhibits tumor growth in a murine model of Ewing's sarcoma. The nonviral delivery system uses a poly-iso-hexyl-cyanoacrylate (PIHCA)-containing polycation (chitosan) to bind and protect the AS-ON. No antitumor effect is observed using a control oligonucleotide sequence. We found here that injection of the free AS-ON stimulates tumor growth independently of its sequence and that this stimulation is abolished in the presence of nanosphere-chitosan, which exerts with the oligonucleotides a specific inhibitory effect on tumor growth. The stimulation of tumor growth is likely to be due to a polyanionic effect; indeed, a similar stimulatory response is observed upon treatment with dextran sulfate and heparin in vivo. These results suggest that ON loaded onto nanosphere-chitosan provides efficient and tumor-specific delivery, and provides protection against a polyanionic secondary effect.

Postnatal weight and height growth velocities at different ages between birth and 5 y and body composition in adolescent boys and girls.

BACKGROUND: Rapid weight gain in the first years of life is associated with adult obesity. Whether there are critical windows for this long-term effect is unclear. OBJECTIVE: The objective was to study anthropometric measures in adolescence by sex according to weight and height growth velocities at different ages between birth and 5 y. DESIGN: Anthropometric measures, including fat and fat-free mass by bipodal impedancemetry, were measured in 468 adolescents aged 8-17 y. We retrospectively collected early infancy data and individually estimated weight and height growth velocities in 69.4% of them using a mathematical model. Associations between birth variables, growth velocities, and anthropometric measures in adolescence were studied. RESULTS: Weight growth velocity at 3 mo was associated with overweight (odds ratio for a 1-SD increase: 1.52; 95% CI: 1.04, 2.22), fat mass, and waist circumference in adolescence in both sexes and with fat-free mass in boys (r = 0.29, P < 0.001) but not in girls (r = -0.01, NS). Weight growth velocities after 2 y were associated with all anthropometric measures in adolescence, in both sexes. Between 6 mo and 2 y, weight growth velocities were significantly associated only with adolescent height in boys; in girls, associations with fat mass in adolescence were weaker. CONCLUSION: Our results support the hypothesis of 2 critical windows in early childhood associated with the later risk of obesity: up to 6 mo and from 2 y onward. The study of the determinants of growth during these 2 periods is of major importance for the prevention of obesity in adolescence.

Interrelationships of quantitative asthma-related phenotypes in the Epidemiological Study on the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness, and Atopy.

BACKGROUND: Delineating asthma subphenotypes is of interest to understand the cause of the disease. Few studies have addressed the interrelationships of quantitative asthma-related traits. OBJECTIVE: We sought to study the interrelationships of allergy markers and FEV(1) in relation to asthma and sex in children and adults. METHODS: Total IgE levels, skin prick test (SPT) positivity, eosinophil counts, and FEV(1) were assessed in 299 asthmatic cases (children and adults) recruited in chest clinics and 309 nonasthmatic population-based control subjects in the French Epidemiological Study on the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness, and Atopy. RESULTS: Allergy parameters were significantly higher in asthmatic cases than in control subjects for children and adults and for both sexes. Sex and age modified the pattern of concordance of high IgE levels, SPT positivity, and eosinophilia among asthmatic cases, with the greatest overlap in male children (64%) and the lowest in male adults (18%). Patterns of change over the lifespan of IgE levels, eosinophil counts, and FEV(1)/height(2) varied, with the acceleration of FEV(1) decrease being particularly evident in asthmatic adults. In adult cases and control subjects, SPT positivity (particularly to indoor allergens) was significantly related to IgE levels but not to eosinophil counts. The association of eosinophil counts with IgE levels was evident only in children. Environmental factors (smoking, pets, and country living) did not alter the patterns observed. CONCLUSIONS: Each allergy-related phenotype showed a distinct relation with asthma, with the role for eosinophils being different than that for IgE levels and SPT responses. CLINICAL IMPLICATIONS: Taking age and sex into account is essential for understanding the interrelationships of the various allergy-related phenotypes to asthma status.

Efficacy of siRNA nanocapsules targeted against the EWS-Fli1 oncogene in Ewing sarcoma.

The EWS-Fli1 fusion gene encodes for a chimeric oncogenic transcription factor considered to be the cause of the Ewing sarcoma. The efficiency of small interfering RNAs (siRNAs) targeted toward the EWS-Fli1 transcript (at the junction point type 1) was studied, free or encapsulated into recently developed polyisobutylcyanoacrylate aqueous core nanocapsules. Because this mRNA sequence is only present in cancer cells, it therefore constituted a relevant target. Studies of the intracellular penetration by confocal microscopy in NIH/3T3 EWS-Fli1 cells showed that nanocapsules improved the intracellular penetration of siRNA with mainly a cytoplasmic localization. These biodegradable siRNA-loaded nanocapsules were then tested in vivo on a mice xenografted EWS-Fli1-expressing tumor; they were found to trigger a dose-dependant inhibition of tumor growth after intratumoral injection. A specific inhibition of EWS-Fli1 was observed, too. These findings now open new prospects for the treatment of experimental cancers with junction oncogenes.

Asthma severity is associated with body mass index and early menarche in women.

Asthma severity in relation to body mass index (BMI) has rarely been studied. The relation between BMI and asthma severity was studied by sex in 366 adults with asthma from the Epidemiological Study on the Genetics and Environment of Asthma, a case-control and family study on asthma. Factors related to asthma severity and BMI such as smoking, FEV(1), bronchial hyperresponsiveness, and dyspnea were taken into account. The influence of early menarche was studied to assess the potential role of hormonal factors. Clinical asthma severity in the last 12 months was assessed by a score (0-7) based on the frequency of asthma attacks, persisting symptoms between attacks, and hospitalization. Asthma severity, which was unrelated to sex, increased with BMI in women (p = 0.0001) but not in men (p = 0.3). In women, the association remained after adjustment for age, FEV(1), smoking habits, and BMI-adjusted dyspnea and taking into account familial dependence (p = 0.0001). The association between BMI and severity was stronger in women with early menarche than in women without early menarche (p interaction = 0.02). Findings support the hypothesis of hormonal factors involved in the severity of asthma.

A Bayesian analysis of pharmacoeconomic data from a clinical trial on schizophrenia.

Pharmacoeconomic studies are performed in a higher frequency to assess the economic interest of new drugs. However, a standard methodology does not still completely exist. We present here the principles and results of a cost-effectiveness Bayesian analysis on data from 146 patients (interim analysis) collected during a clinical trial. This trial was originally planned to enrol 245 patients with predominantly negative schizophrenia symptoms and involved four treatment groups (a new treatment given at low dose and high dose, a comparator and a placebo). First, some prior distributions of the cost-effectiveness ratio were numerically deduced from the effectiveness parameter clinical priors (based on investigators' opinions and questionnaires before going to blind breaking) and from cost function priors. The costs taken into account were hospitalizations, sick leave days, treatments, visits to the doctor, laboratory exams and suicide attempts. The effectiveness parameter was the change from baseline on SANS (scale for the assessment of negative symptoms). Posterior distributions were elaborated for the cost-effectiveness ratio by combining the cost-effectiveness ratio priors and likelihood together using the Bayes theorem. Results lead to a conclusion in favour of the new treatment given at high dose.

Two-treatment comparison based on joint toxicity and efficacy ordered alternatives in cancer trials.

The primary goal of anticancer treatments is to attain efficacy, however toxicity could affect the course of the therapy. Methods have been proposed for comparing two treatments on the basis of the joint distribution for safety and efficacy outcomes, but they do not take into account the cumulative doses of drugs (chemotherapy) or radiation (radiotherapy) received by each patient. Moreover, these methods assume a parametric form for the joint distribution. In this paper we define a multi-dimensional parameter including toxicity and efficacy outcomes and the dose at which one, none or both occur. Each patient is classified into an ordered category depending on the order of occurrence of these two criteria: the sooner the patient benefits from efficacy and/or the later he/she experiences toxicity, the better is the treatment. We then apply likelihood ratio tests with ordered alternatives. This procedure requires constrained maximum likelihood estimation via isotonic regression. A large set of simulations compares the proposed tests to other more usual tests and the results show a good power and a satisfactory type I error control. Our approach is illustrated with a multi-centre randomized clinical trial involving patients with metastatic non-seminomatous germ cell tumours.

Methodologic aspects of the quantification of skin prick test responses: the EGEA study.

BACKGROUND: The expression of responses of allergy skin prick tests is not standardized. Usual definitions of atopy are not quantitative. OBJECTIVE: We sought to perform a biometric analysis of responses to various allergens to propose synthetic, quantitative indices independent of the heterogeneity of responses to various allergens. METHODS: Adults (N = 1286) from the Epidemiological Study on the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness, and Atopy (EGEA) were included in the analysis. The first step, conducted for 678 subjects with at least 1 wheal >0, was to perform a standardization of wheal diameters to obtain comparable figures for 10 allergens through use of the means of the squares of wheal size as a scaling factor. The second step was a factor analysis of the standardized responses conducted not only for all subjects but also separately for asthmatic case and nonasthmatic control subjects. Finally, the strength of the link between various dichotomous and quantitative scores was assessed with multiRAST, total IgE, and asthma. Analyzed quantitative scores were based on the number of positive responses and on the nonstandardized and standardized sizes of the wheals. RESULTS: The standardization was efficient. Among asthmatic subjects but not other subjects, factor analysis evidenced a pattern with 3 factors, corresponding to outdoor, indoor, and mold allergens. The link study showed that all scores performed very similarly. CONCLUSION: The number of positive tests is a quantitative score with valid biometric properties. It should be used more widely in clinical settings and in epidemiology to assess the severity of atopy.

Non-parametric optimal design in dose finding studies.

We describe a non-parametric optimal design as a theoretical gold standard for dose finding studies. Its purpose is analogous to the Cramer-Rao bound for unbiased estimators, i.e. it provides a bound beyond which improvements are not generally possible. The bound applies to the class of non-parametric designs where the data are not assumed to be generated by any known parametric model. Whenever parametric assumptions really hold it may be possible to do better than the optimal non-parametric design. The goal is to be able to compare any potential dose finding scheme with the optimal non-parametric benchmark. This paper makes precise what is meant by optimal in this context and also why the procedure is described as non-parametric.