General regression model: A "model-free" association test for quantitative traits allowing to test for the underlying genetic model.

Most genome-wide association studies used genetic-model-based tests assuming an additive mode of inheritance, leading to underpowered association tests in case of departure from additivity. The general regression model (GRM) association test proposed by Fisher and Wilson in 1980 makes no assumption on the genetic model. Interestingly, it also allows formal testing of the underlying genetic model. We conducted a simulation study of quantitative traits to compare the power of the GRM test to the classical linear regression tests, the maximum of the three statistics (MAX), and the allele-based (allelic) tests. Simulations were performed on two samples sizes, using a large panel of genetic models, varying genetic models, minor allele frequencies, and the percentage of explained variance. In case of departure from additivity, the GRM was more powerful than the additive regression tests (power gain reaching 80%) and had similar power when the true model is additive. GRM was also as or more powerful than the MAX or allelic tests. The true simulated model was mostly retained by the GRM test. Application of GRM to HbA1c illustrates its gain in power. To conclude, GRM increases power to detect association for quantitative traits, allows determining the genetic model and is easily applicable.

Gamma-glutamyltransferase, fatty liver index and hepatic insulin resistance are associated with incident hypertension in two longitudinal studies.

OBJECTIVE: We hypothesized that liver markers and the fatty liver index (FLI) are predictive of incident hypertension and that hepatic insulin resistance plays a role. METHODS: The association between liver markers and incident hypertension was analysed in two longitudinal studies of normotensive individuals, 2565 from the 9-year data from an epidemiological study on the insulin resistance cohort and the 321 from the 3-year 'Relationship between Insulin Sensitivity and Cardiovascular disease' cohort who had a measure of endogenous glucose production. The FLI is calculated from BMI, waist circumference, triglycerides and gamma-glutamyltransferase (GGT) and the hepatic insulin resistance index from endogenous glucose production and fasting insulin. RESULTS: The incidence of hypertension increased across the quartiles groups of both baseline GGT and alanine aminotransferase. After adjustment for sex, age, waist circumference, fasting glucose, smoking and alcohol intake, only GGT was significantly related with incident hypertension [standardized odds ratio: 1.21; 95% confidence interval (1.10-1.34); P = 0.0001]. The change in GGT levels over the follow-up was also related with an increased risk of hypertension, independently of changes in body weight. FLI analysed as a continuous value, or FLI at least 60 at baseline were predictive of incident hypertension in the multivariable model. In the RISC cohort, the hepatic insulin resistance index was positively related with the risk of 3-year incident hypertension [standardized odds ratio: 1.54 (1.07-2.22); P = 0.02]. CONCLUSION: Baseline GGT and FLI, as well as an increase in GGT over time, were associated with the risk of incident hypertension. Enhanced hepatic insulin resistance predicted the onset of hypertension and may be a link between liver markers and hypertension.

Impact of statistical models on the prediction of type 2 diabetes using non-targeted metabolomics profiling.

OBJECTIVE: Characterizing specific metabolites in sub-clinical phases preceding the onset of type 2 diabetes to enable efficient preventive and personalized interventions. RESEARCH DESIGN AND METHODS: We developed predictive models of type 2 diabetes using two strategies. One strategy focused on the probability of incidence only and was based on logistic regression (MRS1); the other strategy accounted for the age at diagnosis of diabetes and was based on Cox regression (MRS2). We assessed 293 metabolites using non-targeted metabolomics in fasting plasma samples of 1,044 participants (including 231 incident cases over 9 years) used as training population; and fasting serum samples of 128 participants (64 incident cases versus 64 controls) used as validation population. We applied a LASSO-based variable selection aiming at maximizing the out-of-sample area under the receiver operating characteristic curve (AROC) and integrated AROC. RESULTS: Sixteen and 17 metabolites were selected for MRS1 and MRS2, respectively, with AROC = 90% and 73% in the training and validation populations, respectively for MRS1. MRS2 had a similar performance and was significantly associated with a younger age of onset of type 2 diabetes (ß = -3.44 years per MRS2 SD in the training population, p = 1.56 × 10(-7); ß = -4.73 years per MRS2 SD in the validation population, p = 4.04 × 10(-3)). CONCLUSIONS: Overall, this study illustrates that metabolomics improves prediction of type 2 diabetes incidence of 4.5% on top of known clinical and biological markers, reaching 90% in total AROC, which is considered the threshold for clinical validity, suggesting it may be used in targeting interventions to prevent type 2 diabetes.

Gain-of-function Prolactin Receptor Variants Are Not Associated With Breast Cancer and Multiple Fibroadenoma Risk.

CONTEXT: In a cohort of 95 women with multiple breast fibroadenomas (MFAs), we recently identified patients harboring germline heterozygous variants of the prolactin receptor (PRLR) exhibiting constitutive activity (PRLRI146L and PRLRI176V). OBJECTIVE: This study sought to better delineate the potential role of PRLR gain-of-function variants in benign and malignant mammary tumorigenesis. DESIGN: This was an observational study and transgenic mouse model analysis. SETTING: The study took place at the Department of Endocrinology, Reproductive Disorders and Rare Gynecologic Diseases, Pitié Salpêtrière, Paris, and Inserm Unit 1151, Paris. PATIENTS OR OTHER PARTICIPANTS: We generated a second MFA cohort (n = 71) as well as a group of control subjects (n = 496) and a cohort of women with breast cancer (n = 119). We also generated two transgenic mouse models carrying the coding sequences of human PRLRI146L or PRLRWT. INTERVENTION: We aimed to determine the prevalence of PRLR variants in these three populations and to uncover any association of the latter with specific tumor pattern, especially in patients with breast cancer. RESULTS: This study did not highlight a higher prevalence of PRLR variants in the MFA group and in the breast cancer group compared with control subjects. Transgenic mice expressing PRLRI146L exhibited very mild histological mammary phenotype but tumors were never observed. CONCLUSION: PRLRI146L and PRLRI176V variants are not associated with breast cancer or MFA risk. However, one cannot exclude that low but sustained PRLR signaling may facilitate or contribute to pathological development driven by oncogenic pathways. Long-term patient follow-up should help to address this issue.

Longitudinal association of antidepressant medication use with metabolic syndrome: Results of a 9-year follow-up of the D.E.S.I.R. cohort study.

OBJECTIVE: To examine longitudinal associations between antidepressant medication use and the metabolic syndrome (MetS). METHODS: 5014 participants (49.8% were men) from the D.E.S.I.R. cohort study, aged 30-65 years at baseline in 1994-1996, were followed over 9 years at 3-yearly intervals (1997-1999, 2000-2002, and 2003-2005). Antidepressant use and MetS, defined by the National Cholesterol Education Program Adult Treatment Panel III criteria (NCEP-ATP III) and the American Heart Association and the National Heart, Lung and Blood Institute (AHA/NHLBI) criteria, were assessed concurrently at four medical examinations. RESULTS: In fully-adjusted longitudinal logistic regression analyses based on generalized estimating equations, antidepressant users had a 9% (p=0.011) and a 6% (p=0.036) greater annual increase in the odds of having the MetS defined by NCEP-ATP III and AHA/NHLBI criteria respectively. Sex-specific analyses showed that this association was confined to men only. When the different types of antidepressant were considered, men who used selective serotonin reuptake inhibitors (SSRIs), imipramine type antidepressants or "other" antidepressants had a 52% (p=0.028), 31% (p=0.011), and 16% (p=0.016) greater annual increase in the odds of having the MetS over time compared to non-users, respectively. These associations depended on the definition of the MetS. CONCLUSIONS: Our longitudinal data showed that antidepressant use was associated with an increased odds of having the MetS in men but not in women and this was mainly for SSRIs, imipramine type and "other" antidepressants. People on antidepressants may need to be checked regularly for the elements of the metabolic syndrome treatable by change in diet, physical activity and/or by medication therapy.

Metabolomic Profile of Low-Copy Number Carriers at the Salivary α-Amylase Gene Suggests a Metabolic Shift Toward Lipid-Based Energy Production.

Low serum salivary amylase levels have been associated with a range of metabolic abnormalities, including obesity and insulin resistance. We recently suggested that a low copy number at the AMY1 gene, associated with lower enzyme levels, also increases susceptibility to obesity. To advance our understanding of the effect of AMY1 copy number variation on metabolism, we compared the metabolomic signatures of high- and low-copy number carriers. We analyzed, using mass spectrometry and nuclear magnetic resonance (NMR), the sera of healthy normal-weight women carrying either low-AMY1 copies (LAs: four or fewer copies; n = 50) or high-AMY1 copies (HAs: eight or more copies; n = 50). Best-fitting multivariate models (empirical P < 1 × 10-3) of mass spectrometry and NMR data were concordant in showing differences in lipid metabolism between the two groups. In particular, LA carriers showed lower levels of long- and medium-chain fatty acids, and higher levels of dicarboxylic fatty acids and 2-hydroxybutyrate (a known marker of glucose malabsorption). Taken together, these observations suggest increased metabolic reliance on fatty acids in LA carriers through ß- and ω-oxidation and reduced cellular glucose uptake with consequent diversion of acetyl-CoA into ketogenesis. Our observations are in line with previously reported delayed glucose uptake in LA carriers after starch consumption. Further functional studies are needed to extrapolate from our findings to implications for biochemical pathways.

[French shift workers seen at health centres have an increased risk of lipid disorders]. / Perturbation du métabolisme lipidique chez des travailleurs postés consultants de centres d'examens de santé.

AIMS: To describe cardiovascular risk factors and metabolic disturbances in a French population including shift workers and study whether possible changes were noticeable after non-shift to shift work transition within the last five years. METHODS: The study population included 4764 attendees of two health examinations (5 years apart), between January 1996 and October 2008, in 11 health examination centres. Clinical, biological and metabolic factors together with their changes over a five-year period were compared between attendees who kept a non-shift daytime job, those who kept working shift and those who switched from non-shift daytime to shift work over the last 5 years. RESULTS: At baseline, working shift was, independently of lifestyle or BMI, significantly related to more elevated plasma triglycerides (ß=0.04, P=0.05) and rate of hypertriglyceridemia (ß=0.27, P=0.01), lower plasma HDL-C levels (ß=-2.03, P=0.006) and less hypertension (ß=-0.25, P=0.01) compared to non-shift daytime work. In men, a slightly more elevated yet non significant proportion of hypertriglyceridemia was observed with the transition from non-shift daytime to shift work within the last 5 years in comparison to men who kept a non-shift daytime job (13.9% vs. 11.0% P=0.17). CONCLUSION: Our results are in agreement with previous studies showing a deleterious effect of shift work on lipid metabolism. In our population, triglycerides and HDL-C levels were the main parameters negatively influenced by shift work. Consequently, a regular biological monitoring together with the promotion of healthy behaviours should be provided to shift workers before negative consequences of working shift become noticeable.

Plasma Copeptin, AVP Gene Variants, and Incidence of Type 2 Diabetes in a Cohort From the Community.

CONTEXT: Experimental data support a role for vasopressin in metabolic disorders. OBJECTIVE: We investigated associations of plasma copeptin, a surrogate of vasopressin, and of allelic variations in the arginine vasopressin-neurophysin II gene with insulin secretion, insulin sensitivity, and the risk for impaired fasting glucose (IFG) and type 2 diabetes mellitus (T2DM). DESIGN, SETTING, AND PARTICIPANTS: We studied 5110 unrelated French men and women from a prospective cohort of the general population (Data from Epidemiological Study on the Insulin Resistance Syndrome cohort, 9-y follow-up). Six single nucleotide polymorphisms were genotyped. MAIN OUTCOME MEASURE: Incidence of IFG or T2DM during follow-up. RESULTS: The incidence of hyperglycemia (IFG/T2DM) during follow-up by quartiles of baseline plasma copeptin was 11.0% (Q1), 14.5% (Q2), 17.0% (Q3), and 23.5% (Q4), log-rank test P = .003. Participants in the upper quartile of plasma copeptin had significantly lower insulin sensitivity (homeostasis model assessment index) at baseline and during follow-up, as compared with other participants. Cox proportional hazards regression analyses showed significant associations of the CC genotype of rs6084264, the TT genotype of rs2282018, the C-allele of rs2770381, and the CC genotype of rs1410713 with the incidence of hyperglycemia. The genotypes associated with an increased risk of hyperglycemia were also associated with increased plasma copeptin in men but not in women. CONCLUSIONS: High plasma copeptin was associated with reduced insulin sensitivity and an increased risk for IFG/T2DM diabetes in this community-based cohort. Moreover, in men, allelic associations support a causal role for vasopressin in these disorders.

[Promote better nutritional behaviours among shift workers with night shift]. / Promouvoir un meilleur comportement nutritionnel chez les travailleurs postés avec horaires de nuit.

AIM: Shift work, especially including a night shift, is associated with degradation of physical, social and psychosocial health as well as poor well-being. Food imbalance and low physical activity contributed to the negative effects on health. Our objective was to promote a healthier nutritional behaviour according to the French national nutrition and health program recommendations (PNNS). METHODS: A one-year nutritional intervention with personalised dietetic counselling was proposed to 235 shift workers with night shift who came for a health prevention exam in one of the centres of the Institut Inter-Régional pour la Santé between 2009 and 2011. The intervention was three dietary interviews: at baseline with definition of goal setting, at 3 months for advice and support and at one-year for the evaluation. At 6 months, a personalised reminder letter was send. Compliance with the PNNS recommendations and level of physical activity were evaluated at baseline and at one-year by a self-administered questionnaire. Changes between baseline and follow-up were compared by paired t-tests or McNemar-tests. RESULTS: The rate of follow-up was 57.4%. At the end of the study, subjects improved their compliance with PNNS guidelines concerning sweetened products (P<0.001), water (P=0.02) and salt (P=0.05), increased their leisure physical activity (P=0.001) and decreased their daily energy intakes (P<0.001). CONCLUSION: A structured intervention can improve nutritional behaviours of shift workers. This intervention enabled to inform and alert on the risk related to this work schedule and promote better nutritional behaviours.

[Determination of full blood count normal reference values for adults in France]. / Étude des valeurs normales de l'hémogramme chez l'adulte: un besoin pour une meilleure interprétation et pour l'accréditation du laboratoire.

The full blood count (FBC) is the most prescribed laboratory test in France. Due to the lack of data, there is a great variability in reference values of the FBC, between medical laboratories. The aim of this work was to provide normal reference values for FBC in adults. These normal values were defined in a population of 33 258 healthy adults, 19 612 men and 13 646 women. These values were determined after excluding subjects having conditions in order to modify, either directly or indirectly, FBC parameters. For each parameter, we provide results for values of standard parameters, by sex and age, from 16 to 69 years. In addition, we present FBC values from a population of 339 subjects aged over 69 years with no comorbidities. These normal values are proposed to be used in everyday practice. They make it possible to distinguish, without ambiguity, a normal situation from a pathological situation. Moreover, they can be applied to the entire metropolitan France.

Full blood count normal reference values for adults in France.

AIMS: To determine full blood count (FBC) normal reference values for adults. METHODS: FBC normal values for healthy adults were defined, after establishing preanalytical conditions, in a population of 33 258 subjects, 19 612 men and 13 646 women. The values were established after excluding from this population all people having conditions liable to modify, directly or indirectly, FBC parameters. RESULTS: Results for values of standard parameters are provided in detail for each parameter, by sex and by age group from 16 to 69 years of age. In addition, we present FBC values from a population of 339 subjects aged over 69 years with no comorbidities. CONCLUSIONS: These normal values are proposed for use in everyday practice. They make it possible to distinguish, without ambiguity, a normal situation from a pathological situation. Moreover, they might be used over all mainland France.

Deprivation and health risk indicators in full-time permanent workers.

BACKGROUND: Association between deprivation and health is well established, particularly among unemployed or fixed-term contract or temporary contract subjects. This study aimed to assess if this relationship existed as well in full-time permanent workers. METHODS: Biometrical, biological, behavioural and psychosocial health risk indicators and an individual deprivation score, the Evaluation of Precarity and Inequalities in Health Examination Centres score, were recorded from January 2007 to June 2008, in 34 905 full-time permanent workers aged 18-70 years, all volunteers for a free health examination. Comparisons of the behavioural, metabolic, cardiovascular and health risk indicators between quintiles of the deprivation score with adjustments on age and socioeconomic categories were made by covariance analysis or logistic regression. RESULTS: For both genders, degradation of nutritional behaviours, metabolic and cardiovascular indicators and health appeared gradually with deprivation, even for deprivation score usually considered as an insignificant value. The absence of only one social support or one social network was associated with a degradation of health. Full-time permanent workers with the poorest health risk indicators had more frequent social exclusion signs. These results were independent of socioeconomic categories and age. CONCLUSION: Understanding how deprivation influences health status may lead to more effective interventions to reduce social inequalities in health. The deprivation Evaluation of Precarity and Inequalities in Health Examination Centres score is a relevant tool to detect subjects who could benefit from preventive interventions. Our findings suggest that this deprivation score should be used as a health risk indicator even in full-time permanent workers. Assessing deprivation is useful to design and evaluate specific intervention programmes.

[Good reproducibility and validity of a self-administered questionnaire evaluating adherence to the French national nutrition and health program recommendations]. / Reproductibilité et validation satisfaisantes d'un auto-questionnaire pour évaluer l'atteinte des repères du Programme National Nutrition Santé

OBJECTIVES: To study the reproducibility and validity of a French self-administered questionnaire (NAQAPNNS) evaluating the adequation of a subject with the French national nutrition and health program recommendations. METHODS: The reproducibility was estimated by weighted kappa in 48 subjects working in the administrative departments of the head office of the Institut Inter Régional pour la Santé in Tours aged from 21 to 63 years who filled the questionnaire NAQAPNNS twice with a two weeks interval. The validity was assessed in 524 hyperglycaemic subjects (fasting plasma glucose between 1.10g/l and 1.25g/l) aged from 25 to 70 years against a seven-day dietary recall using the Kruskall-Wallis test. Agreement between self-administration of the questionnaire and dietetic interview was evaluated by weighted kappa. RESULTS: The reproducibility was "good" (kappa≥0.67) except for recommendations on breads, cereals, potatoes and legumes (kappa=0.50) and sweetened foods consumption (kappa=0.54) which showed only "satisfactory" reproducibility. For each recommendation, subjects who reached it had dietary intakes closer to dietary references intakes (P<0.03). The agreement between self-administration and dietetic interview was "good" (kappa≥0.63) except for recommendations on added fats (kappa=0.41) and salt (kappa=0.50) consumption which were only "satisfactory". DISCUSSION: The NAQAPNNS questionnaire is a consistent and reproducible tool to evaluate adequation of a subject with French national nutritional recommendations. CONCLUSION: The self-administered questionnaire NAQAPNNS can be used in clinical practice or in epidemiological studies to detect subjects with a food imbalance and needing specific care.

Novel modeling of reference values of cardiovascular risk factors in children aged 7 to 20 years.

BACKGROUND AND OBJECTIVE: Most of the cardiovascular risk factors strongly associated with obesity and overweight vary with age and gender. However, few reference values are available for healthy European children. Our objective was to establish pediatric reference ranges for waist circumference, systolic and diastolic blood pressures, fasting lipid levels (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides), glucose, and insulin. METHODS: A representative sample of 1976 healthy French individuals (1004 female participants and 972 male participants) aged 7 to 20 years was used to obtain age- and gender-specific normal ranges for each of the above-listed cardiovascular risk factors, based on the Royston and Wright method. RESULTS: Mean waist circumference increased with age in both genders and was slightly higher in males than in females. Whereas systolic blood pressure increased gradually with age, with the increase being steeper in males than in females, no gender effect was found for diastolic blood pressure, which was therefore modeled after pooling males and females. Total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride values varied little with age and gender. Glucose and insulin levels revealed pubertal peaks, which were sharper in females than in males, reflecting the normal insulin resistance during puberty. CONCLUSIONS: These ranges can be used as references for European children to monitor cardiovascular risk factors and to plan interventions and education programs.

Genomewide association study using a high-density single nucleotide polymorphism array and case-control design identifies a novel essential hypertension susceptibility locus in the promoter region of endothelial NO synthase.

Essential hypertension is a multifactorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions. The discovery phase consisted of 1865 cases and 1750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1385 cases and 1246 controls that were genotyped with a custom array of 14 055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial NO synthase gene (odds ratio: 1.54 [95% CI: 1.37-1.73]; combined P=2.58 · 10(-13)). A meta-analysis, using other in silico/de novo genotyping data for a total of 21 714 subjects, resulted in an overall odds ratio of 1.34 (95% CI: 1.25-1.44; P=1.032 · 10(-14)). The quantitative analysis on a population-based sample revealed an effect size of 1.91 (95% CI: 0.16-3.66) for systolic and 1.40 (95% CI: 0.25-2.55) for diastolic blood pressure. We identified in silico a potential binding site for ETS transcription factors directly next to rs3918226, suggesting a potential modulation of endothelial NO synthase expression. Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus.

Blood pressure loci identified with a gene-centric array.

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.

[Age and sex variations of HbA(1C) in a French population without known diabetes aged 6 to 79 years]. / Évolution de l'HbA(1C) en fonction de l'âge et du sexe dans une population française de sujets sans diabète connu âgés de 6 à 79 ans.

HbA(1C) is being used for screening and diagnosing diabetes. We determined mean values of HbA(1C) according to age and sex in a large population without known diabetes, in a wide age range 6-79  years. 5,138 men and women without known diabetes aged 6-79  years participated in a routine health examination provided by their medical insurance. HbA(1C) was assessed on an HPLC analyzer aligned with a DCCT method. HbA(1C) was approximately normally distributed in both men and women. Mean (SD) HbA(1C) were, for men vs women, in percentages 5.3 (0.4) vs 5.2 (0.3), in mmol/mol 34 (5) vs 34 (4) and in estimated blood glucose in mmol/L 5.83 (0.67) vs 5.75 (0.53). HbA(1C) increased with age by 0.08% every 10  years and this was attenuated to a 0.04% increase after adjustment on fasting plasma glucose. Between 15 and 49  years, women had lower values than men (p < 0.0001), but no sex differences were observed before and after this age range. In our population, 0.6% had HbA(1C) greater or equal to 6.5% and 88% (96% of men and 73% of women) of them had fasting plasma glucose greater or equal to 6,1 mmol/L. Threshold of 6.0% selected 2.8% of our population.

Serum concentrations of insulin-like growth factor (IGF)-1 and IGF binding protein-3 (IGFBP-3), IGF-1/IGFBP-3 ratio, and markers of bone turnover: reference values for French children and adolescents and z-score comparability with other references.

BACKGROUND: A reference model for converting serum growth factor and bone metabolism markers into an SD score (SDS) is required for clinical practice. We aimed to establish reference values of serum insulin-like growth factor-1 (IGF-1) and IGF binding protein 3 (IGFBP-3) concentrations and bone metabolism markers in French children, to generate a model for converting values into SDS for age, sex, and pubertal stage. METHODS: We carried out a cross-sectional study of 1119 healthy white children ages 6-20 years. We assessed concentrations of serum IGF-1, IGFBP-3, carboxyterminal telopeptide α1 chain of type I collagen (CrossLaps), and bone alkaline phosphatase concentrations and height, weight, and pubertal stage, and used semiparametric regression to develop a model. RESULTS: A single regression model to calculate the SDSs with an online calculator was provided. A positive relationship was found between SDS for serum IGF-1 and IGFBP-3, IGF/IGFBP-3 mol/L ratio, and anthropometric parameters (P < 0.0001), with slightly greater effects observed for height than for body mass index (BMI). There was a negative relationship between serum CrossLaps concentration and BMI, and a positive relationship between serum CrossLaps concentration and height. A comparison of serum IGF-1 reference databases for children showed marked variation as a function of age and pubertal group; smooth changes with age and puberty were observed only in our model. CONCLUSIONS: This new model for the assessment of SDS reference values specific for age, sex, and pubertal stage may help to increase the diagnostic power of these parameters for the assessment of growth and bone metabolism disorders. This study also provides information about the physiological role of height and BMI for the interpretation of these parameters.

Analytical comparison of three quantitative immunochemical fecal occult blood tests for colorectal cancer screening.

BACKGROUND: The superiority of several immunochemical fecal occult blood tests (I-FOBT) over guaiac-based tests in colorectal cancer screening is now established. The aim of this study was to compare the analytical performance of 3 quantitative I-FOBTs. METHODS: Stool samples from 10 healthy volunteers, initially I-FOBT negative, supplemented with human blood, were used to compare reproducibility and stability of measurement at varying storage temperatures (4°C, 10°C, 20°C, and 30°C) and durations before test analysis (1 to 10 days) for 3 I-FOBTs (New Hemtube/Magstream HT, OC-Auto sampling bottle3/OC-Sensor DIANA, and FOB Gold/SENTiFOB). Concentrations ranging from 0 to 350 µg Hb/g of feces were evaluated. RESULTS: The measurement reproducibility of OC-Sensor was superior to Magstream and far superior to FOB Gold. For all tests, variability was essentially related to sampling. Detected hemoglobin (Hb) levels were substantially lower for all tests at temperatures above 20°C. At 20°C, this loss in concentration was less important with OC-Sensor (significant 1.7% daily decrease vs. 7.4% for Magstream and 7.8% for FOB Gold). At 30°C, daily loss was 8.6% with OC-Sensor, whereas after 24 hours, only 30% of the original Hb was detected with FOB Gold, compared to 70% with Magstream. No Hb was detected on day 5 for the latter 2 tests. CONCLUSIONS: About reproducibility and temperature stability, OC-Sensor performed better than Magstream and far better that FOB Gold. IMPACT: Independently of the chosen test, the delay between sampling and test processing should be reduced, the maximal admissible delay depending on ambient temperature.