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Biomedical subjects

A Mallet

Publications and source records attributed to A Mallet.

At least 19 recordsLinked to original sources
PubMed2002

Study of a patient population investigated for excessive daytime sleepiness (EDS).

This study included all patients referred to the out-patient department of our sleep disorders centre from 1993 to 1999 on account of excessive daytime sleepiness (EDS). As a first step, patients in whom a diagnosis was established following appropriate polysomnography were excluded: this included sleep apnea syndrome, increased upper airway resistance syndrome, narcolepsy, periodic movements during sleep or other parasomnia, and epilepsy. Patients regularly taking psychotropic substances or with psychiatric disorders were also excluded. Finally, 128 patients remained in whom no clear diagnosis had been established for EDS, 70 women and 58 men, their ages ranging from 16 to 77 years. They underwent a 48-h recording (night 1-MSLT-night 2-continuous day). The aim of the study was to establish, define and characterise different groups of undiagnosed EDS patients using clinical, electrophysiological and immunological data with the help of hierarchical cluster analysis. Eight groups were characterised: group 1: mild hypersomnia type 1 (n = 11); group 2: hypersomnia frequently associated with HLA type DR2-DQw1 (n = 11); group 3: mild hypersomnia type 2 (n = 28); group 4: morning recovery from disrupted sleep (n = 19); group 5: young "long sleepers with difficulty at waking up" (n = 17); group 6: idiopathic hypersomnia (n = 15); group 7: poor or short sleepers since childhood (n = 8); group 8: older poor sleepers with a late onset of symptoms (n = 19). Characteristic features of these different groups provided consistent and objective arguments leading to a more precise diagnosis for these patients, and helped the initiation of appropriate management and treatment.

Adolescent↗
PubMed2001

Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II Trial.

BACKGROUND: beta-Blockade-induced benefit in heart failure (HF) could be related to baseline heart rate and treatment-induced heart rate reduction, but no such relationships have been demonstrated. METHODS AND RESULTS: In CIBIS II, we studied the relationships between baseline heart rate (BHR), heart rate changes at 2 months (HRC), nature of cardiac rhythm (sinus rhythm or atrial fibrillation), and outcomes (mortality and hospitalization for HF). Multivariate analysis of CIBIS II showed that in addition to beta-blocker treatment, BHR and HRC were both significantly related to survival and hospitalization for worsening HF, the lowest BHR and the greatest HRC being associated with best survival and reduction of hospital admissions. No interaction between the 3 variables was observed, meaning that on one hand, HRC-related improvement in survival was similar at all levels of BHR, and on the other hand, bisoprolol-induced benefit over placebo for survival was observed to a similar extent at any level of both BHR and HRC. Bisoprolol reduced mortality in patients with sinus rhythm (relative risk 0.58, P:<0.001) but not in patients with atrial fibrillation (relative risk 1.16, P:=NS). A similar result was observed for cardiovascular mortality and hospitalization for HF worsening. CONCLUSIONS: BHR and HRC are significantly related to prognosis in heart failure. beta-Blockade with bisoprolol further improves survival at any level of BHR and HRC and to a similar extent. The benefit of bisoprolol is questionable, however, in patients with atrial fibrillation.

Adrenergic beta-Antagonists↗
PubMed2001

Anticoagulant (fluindione)-aspirin combination in patients with high-risk atrial fibrillation. A randomized trial (Fluindione, Fibrillation Auriculaire, Aspirin et Contraste Spontané; FFAACS).

BACKGROUND: A combination of low-dose aspirin with anticoagulants may provide better protection against thromboembolic events compared to anticoagulants alone in high-risk patients with atrial fibrillation. OBJECTIVE: Evaluation of the preventive efficacy against nonfatal thromboembolic events and vascular deaths of the combination of the oral anticoagulant fluindione and aspirin (100 mg) in patients with high-risk atrial fibrillation. METHODS: A multicenter, placebo-controlled, double-blind, randomized trial was conducted at 49 investigating centers in France. Atrial fibrillation patients with a previous thromboembolic event or older than 65 years and with either a history of hypertension, a recent episode of heart failure or decreased left ventricular function were included in the study. Patients were treated with fluindione plus placebo (i.e. anticoagulant alone) or fluindione plus aspirin (i.e. combination therapy), with an international normalized ratio target of between 2 and 2.6. The combined primary endpoint was stroke (ischemic or hemorrhagic), myocardial infarction, systemic arterial emboli or vascular death. The secondary endpoint was the incidence of hemorrhagic complications. RESULTS: The 157 participants (average age 74 years; 52% women; 42% with paroxysmal atrial fibrillation) were followed for an average of 0.84 years. Three nonfatal thromboembolic events were observed (1 in the anticoagulation group, 2 in the combination group) and 6 patients died (3 in the anticoagulation group, 3 in the combination group), none of them from a thromboembolic complication. However, 3 deaths were secondary to severe hemorrhagic complications (1 in the anticoagulation group, 2 in the combination group). Nonfatal hemorrhagic complications occurred more often in the combination group (n = 10, 13.1%) compared to the anticoagulation group (n = 1, 1.2%) (p = 0.003). CONCLUSION: The combination of aspirin with anticoagulant is associated with increased bleeding in elderly atrial fibrillation patients. The effect on thromboembolism and the overall balance of benefit to risk could not be accurately assessed in this study due to the limited number of ischemic events.

Administration, Oral↗
PubMed2000

A multi-state model for evolution of intensive care unit patients: prediction of nosocomial infections and deaths.

Nosocomial (hospital-acquired) infections are very frequent in intensive care units (ICU). The risk of death after severe infection is high, but the precise rate of death in ICU attributable to nosocomial infection is not known. The goal of this project was to build a statistical model to predict the occurrence of nosocomial infections in ICU and the outcome of the patients. We collected data on 676 consecutive patients admitted to an ICU for more than 24 hours between 1993 and 1996. The following data were collected for each patient: history; clinical examination at entry; subsequent infections; outcome. A multi-state heterogeneous semi-Markov model was determined and then validated; the initial data set was randomly split into two groups: two-thirds (450 patients) to build the model and one-third (226 patients) to validate it. The model defined five states: ICU admission; first simple infection; first complicated infection; death, and discharge from the ICU. Transitions between these states determined nine different events. The global model of patient histories can be divided into nine survival models, each corresponding to one of these events. The possible events from a given state were considered to be competing. Since many risk factors induced non-proportional hazard functions, piecewise exponential models were used to model event occurrence. The effect of continuous covariates on hazard functions has been described with a non-parametric method that enables non-linear relations to be shown. Among other things, the model allows patients' post-admission histories to be predicted from data available at ICU admission. The bootstrap estimator of the attributable risk of death due to simple or complicated nosocomial infections is 44.2 percent (95 percent CI 26.0-61.6 percent). We were also able to characterize the most highly exposed patients, those who comprise the high-risk group on whom prevention efforts must be focused.

Cross Infection↗
PubMed2000

A new approach for rapid detection and typing of serum monoclonal components.

When used independently, none of the routine methods to explore serum monoclonal components (MC), including: serum protein electrophoresis (SPE), immunoelectrophoresis (IEP), kappa to lambda ratio (KLR) and immunofixation (IFE), provides a comprehensive quantitative and qualitative identification of the MC. In the past few years the concept of 'protein profile', based on immunonephelometric quantifications of serum proteins, has become widely used. It consists of a qualitative and quantitative graphic representation of numerous serum proteins including immunoglobulins. Aim of study was to develop a multidimensional model based exclusively on protein profiles labeled the protein profile prediction method (PPPM) to improve routine MC detection and typing. Serum samples from 127 hospitalized patients and 99 healthy blood donors were submitted to all of the following: SPE, IFE, KLR and a protein profile (which included IgM, IgA, IgG, kappa and lambda chain detections and quantification). The presence of a MC using IFE was chosen as the gold standard. Healthy donors and patients were randomly divided into two groups defined as testing and validation groups. A logistic model was designed based on the protein profiles of the testing group leading to the determination of a threshold value (called Z(r)) for MC detection. It was then tested to detect MC in the validation group. Using IFE, 73 MC were found in the 127 hospitalized patients. Using the threshold value for MC detection of Z(r)=1.86, the PPPM showed greater sensitivity (94.6%) in detecting a MC compared to either SPE (64.8%) or KLR (89.2%). This result was obtained without diminished specificity (80.8%). The association of SPE or KLR to PPPM did not significantly increase the sensitivity of the PPPM. In the validation group, for samples which had a high predictive probability of a MC using PPPM, the correct MC typing was identified in up to 77% of sera using PPPM only. These results may be interesting in helping to determine when supplementary IFE analysis is required to qualitatively analyze a MC. PPPM allows MC detection with great sensitivity. The immune protein profile dramatically increases the sensitivity of either SPE and/or KLR in detecting MC and may also allow heavy and light chain typing.

Antibodies, Monoclonal↗
PubMed2000

Prediction of fluindione maintenance dosage hampered by large intraindividual variability.

In a previous study, the authors proposed a method to individualize fluindione dosage regimen, based on a pharmacokinetic/pharmacodynamic model describing the evolution of the International Normalized Ratio (INR). In this method, daily maintenance dosage for a target INR depends on the product of individual Cl and C50. The present work shows the results of a follow-up study in 50 patients for whom target INR was 2.5. INR measurements and dosage regimens were recorded both during hospital stay and during the 1st month of treatment. Patients were defined as equilibrated after 1 month if the last two INRs were in the range 1.5-3.5 under a stable dosage regimen. Actual maintenance dose was compared with the dose predicted using the three first INRs measured in the hospital. Intraindividual variability of Cl*C50 between hospital stay and after 1 month was evaluated. After 1 month, only 27 patients (54%) were equilibrated. Actual maintenance dose varied from 5 to 30 mg daily. There was no bias between predicted and actual maintenance dose (1.4 mg), but a large root mean squared error (8 mg) was found. The intraindividual variability in Cl*C50 between hospital and maintenance regimen was high (93%), which may explain the dispersion in the predicted maintenance dose.

Anticoagulants↗
PubMed2000

Raised saturated-fat intake worsens vascular function in virgin and pregnant offspring of streptozotocin-diabetic rats.

Adult offspring of severely diabetic pregnant rats are insulin resistant and display cardiovascular dysfunction. When pregnant they develop mild hyperglycaemia. Diets high in saturated fat have been implicated in the development of cardiovascular disease and vascular dysfunction. In the present study we have determined vascular function in small mesenteric arteries from offspring of normal (OC) and diabetic (OD) rats fed standard chow and offspring of diabetic rats fed a diet high in saturated fats (OD-HF) from weaning to adulthood, and throughout their subsequent pregnancies. OD rats displayed an increased sensitivity to noradrenaline (P < 0.05) and impaired sensitivity to the endothelium-dependent vasodilator, acetylcholine. The component of acetylcholine-induced relaxation attributable to endothelium-derived hyperpolarizing factor was reduced in OD-HF rats. Pregnant OD rats also demonstrated impaired maximum relaxation to acetylcholine (pregnant OD rats v. pregnant OC rats P < 0.05). In pregnant OD-HF rats noradrenaline sensitivity was enhanced and endothelium-dependent relaxation further reduced (pregnant OD-HF rats v. pregnant OC rats P < 0.001). The isoprostane, 8-epi-prostaglandin F2alpha, a marker of oxidative stress, was increased in pregnant OD rats (pregnant OD rats v. pregnant OC rats P

Animals↗
PubMed2000

[Checking the Cox model in a real situation].

The Cox model is based on the proportional hazards hypothesis. In real analyses, this hypothesis may not hold. To evaluate the relevance of an interpretation of data using the Cox model, it is important to check this assumption. The major goodness-of-fit methods are reviewed.

Follow-Up Studies↗
PubMed1999

COOH-terminal truncated cardiac myosin-binding protein C mutants resulting from familial hypertrophic cardiomyopathy mutations exhibit altered expression and/or incorporation in fetal rat cardiomyocytes.

Mutations in human cardiac myosin-binding protein C (cMyBP-C) gene are associated with familial hypertrophic cardiomyopathy (FHC), and most of them are predicted to produce COOH-truncated proteins. To understand the molecular mechanism(s) by which such mutations cause FHC, we analyzed (i) the accumulation of human cMyBP-C mutants in fetal rat cardiomyocytes, and (ii) the protein sequence of the human wild-type (wt) cMyBP-C by hydrophobic cluster analysis with the aim of identifying new putative myosin-binding site(s). Accumulation and sarcomeric localization of the wt protein and of four FHC-mutant cMyBP-Cs (E542Q and three COOH-truncated proteins) were studied in cardiomyocytes by immunostaining and confocal microscopy after transfection with myc-tagged constructs. We found that: (i) 10 % of the cells expressing COOH-truncated mutants exhibit an incorporation into the A-band of the sarcomere without any alteration of the myofibrillar architecture versus 76 % of those expressing the wt or E542Q mutant cMyBP-Cs (p<0.001); (ii) 90 % of the cells expressing the truncated mutants show a diffuse localization of these proteins in the cardiomyocytes, out of which 45 % exhibit a significant alteration of the sarcomeric structure (p<0.0001 versus wt); and (iii) the two shortest mutant cMyBP-Cs accumulate at very low levels in fetal rat cardiomyocytes as compared to the wt (p<0.008). Protein sequence analysis indicated that a 45-residue sequence in the NH2-terminal C0 domain of cMyBP-C exhibits a consistent homology (sequence similarity score of 42 %) with a segment of the NH2-terminal domain of myomesin, another myosin-binding protein. This result suggests that the C0 domain of human cMyBP-C contains a novel putative myosin-binding site that could account for the A-band incorporation of the truncated mutants. In addition, the faint accumulation and the diffuse localization of truncated mutants could probably be explained by a low affinity of the C0 domain for myosin. We conclude that COOH-truncated cMyBP-Cs may act as poison polypeptides that disrupt the myofibrillar architecture and result in the defects observed in FHC.

Amino Acid Motifs↗
PubMed1999

Determinants of paradoxical CD4 cell reconstitution after protease inhibitor-containing antiretroviral regimen.

OBJECTIVES: We evaluated the parameters influencing CD4 cell reconstitution after the introduction of highly active antiretroviral therapies in real life, as well as the frequency and the determinants of the discrepancies occurring between virus and CD4 cell count evolution. DESIGN AND METHODS: A total of 317 pre-treated patients starting a protease inhibitor (PI)-containing regimen were prospectively followed for 2 years on an intent-to-treat basis for CD4 cell counts and viral loads. RESULTS: The CD4 cell counts rapidly increased from baseline (50/mm3) by a median of 50/mm3 at month 2 (+0.72 CD4 cells/mm3/day) and up to 137/mm3 at the last follow-up (second slope: +0.16 CD4 cells/mm3/day). Two independent major factors among five parameters tested significantly affected the first phase, which was negatively correlated to the slope of CD4 cell decline before PI initiation, and was positively correlated to baseline CD4 cell counts (P = 0.0001); the second phase was mostly affected by the mean viral load reduction over time (P = 0.0001). Paradoxical CD4 cell reconstitution (15% of cases) was defined by a rapid or slow CD4 cell increase contrasting with a minor or strong viral reduction, respectively. The role of previous CD4 cell decline and the low effect of viral load reduction during the first 2 months explain the early paradoxical CD4 cell responses. The major influence of viral load reduction on the long-term reconstitution, however, reduces such paradoxical responses at 2 years. CONCLUSIONS: Early paradoxical CD4 cell reconstitution after the introduction of a PI are explained by the major influence of previous disease progression on the early CD4 cell increase, whereas the magnitude of viral load reduction over time reduces such paradoxical evolutions in the long term.

Adult↗
PubMed1999

A mutation in the transmembrane/luminal domain of the ryanodine receptor is associated with abnormal Ca2+ release channel function and severe central core disease.

Central core disease is a rare, nonprogressive myopathy that is characterized by hypotonia and proximal muscle weakness. In a large Mexican kindred with an unusually severe and highly penetrant form of the disorder, DNA sequencing identified an I4898T mutation in the C-terminal transmembrane/luminal region of the RyR1 protein that constitutes the skeletal muscle ryanodine receptor. All previously reported RYR1 mutations are located either in the cytoplasmic N terminus or in a central cytoplasmic region of the 5,038-aa protein. The I4898T mutation was introduced into a rabbit RYR1 cDNA and expressed in HEK-293 cells. The response of the mutant RyR1 Ca2+ channel to the agonists halothane and caffeine in a Ca2+ photometry assay was completely abolished. Coexpression of normal and mutant RYR1 cDNAs in a 1:1 ratio, however, produced RyR1 channels with normal halothane and caffeine sensitivities, but maximal levels of Ca2+ release were reduced by 67%. [3H]Ryanodine binding indicated that the heterozygous channel is activated by Ca2+ concentrations 4-fold lower than normal. Single-cell analysis of cotransfected cells showed a significantly increased resting cytoplasmic Ca2+ level and a significantly reduced luminal Ca2+ level. These data are indicative of a leaky channel, possibly caused by a reduction in the Ca2+ concentration required for channel activation. Comparison with two other coexpressed mutant/normal channels suggests that the I4898T mutation produces one of the most abnormal RyR1 channels yet investigated, and this level of abnormality is reflected in the severe and penetrant phenotype of affected central core disease individuals.

Amino Acid Sequence↗
PubMed1999

Identification of heparin oligosaccharides by direct coupling of capillary electrophoresis/ionspray-mass spectrometry.

A direct coupling between capillary electrophoresis (CE) and ionspray (IS) mass spectrometry (MS) has been optimized to identify oligosaccharides obtained by enzymatic digestion of heparin. The separation electrolyte was made compatible with the requirements of a direct coupling using electrolytes made of ammonium acetate buffer, pH 3.5 and 9.2. The different parameters of the CE/IS interface were optimized using a standard mixture of disaccharides: flow rate and composition of the sheath liquid, flow rate of the sheath gas and position of the capillary in the needle. Different combinations of positive or negative CE voltage polarity and positive or negative MS ionization modes were investigated. They allowed for detection orders to be easily reversed and for complementary structural information to be gathered. Finally, the optimized methodology was applied to the separation and characterization of porcine mucosa heparin depolymerized by heparinases II and III.

Carbohydrate Sequence↗
PubMed1999

Outcome of Budd-Chiari syndrome: a multivariate analysis of factors related to survival including surgical portosystemic shunting.

The aim of this study was to assess the factors, including surgical portosystemic shunts, which affect survival in adults with Budd-Chiari syndrome. Multivariate retrospective analysis was performed using characteristics recorded at the time of diagnosis in 120 patients admitted from 1970 to 1992, of whom 82 were treated with surgical portosystemic shunts and 38 received only medical therapy. The 1-, 5-, and 10-year survival rates were 77 +/- 4%, 64 +/- 5%, and 57 +/- 6%, respectively. Survival was significantly better in the subgroup of patients diagnosed after versus before 1985. In both subgroups, and in patients with, as well as in patients without surgical shunts, 4 factors were found to be inversely and independently related to survival: age, response of ascites to diuretics, Pugh score, and serum creatinine. In patients diagnosed since 1985, an index combining these 4 factors allowed to differentiate patients with a good outcome (5-year survival 95%) from those with a poor outcome (5-year survival 62%; P <.05). There was no statistically significant and independent influence of surgical portosystemic shunts on survival. In conclusion, age, severity of liver failure, and presence of refractory ascites are the main prognostic factors in Budd-Chiari syndrome. Increased survival in recent years is consistent with improved management of hypercoagulable states as well as improved general care. It is uncertain whether surgical portosystemic shunting favorably modifies survival. Therefore, we recommend that surgical shunting should be restricted to management of refractory ascites or variceal bleeding in patients with otherwise good prognostic factors.

Adolescent↗
PubMed1999

Familial dilated cardiomyopathy: clinical features in French families.

UNLABELLED: The aims of the study were to analyze the clinical features, the penetrance and the mode of inheritance of 13 French families with dilated cardiomyopathy using diagnostic criteria recently established by a European collaboration. METHODS: Screening consisted of physical examination, ECG and Echo of all the probands first degree relatives (n = 118). Using major Echo criteria [ejection fraction (EF) < 45% or FS < 25% and left ventricular diameter (LVD) > 117% of the predictive value], or combined minor Echo/ECG criteria, relatives were classified as affected, unknown or healthy. RESULTS: (1) Adult affected relatives (n = 31) were identified with major Echo criteria in 74% of cases, and with combined minor Echo/ECG criteria in 26% of cases. (2) In the unknown relatives (n = 21), the most common abnormality was an isolated left ventricular dilation (67%). (3) Mode of inheritance was autosomal dominant (AD) in 11 families and possibly autosomal recessive in two. (4) In AD families, the penetrance was incomplete in adults (72%), age-related (O.R.: 1.3 per 10 years; 95% CI 1.03-1.56) and sex-related [greater in men (87%) than in women (61%), actuarial survival curve: P<0.002]. (5) Mortality related to end stage heart failure was 2.2 times as high as mortality related to sudden death (11% vs. 5%). CONCLUSIONS: (1) In the absence of a specific phenotype of FDC, the characterization of relatives appears more accurate when minor criteria were added. (2) Since high mortality (16%) and incomplete penetrance frequently give rise to small nuclei of clinically affected and alive relatives per family, the accurate model of penetrance that we proposed might be helpful in the future to enhance the statistical power of linkage analysis in this disease.

Adult↗
PubMed1999

Drug-drug pharmacodynamic interaction detection by a nonparametric population approach. Influence of design and of interindividual variability.

Population approaches are appealing methods for detecting then assessing drug-drug interactions mainly because they can cope with sparse data and quantify the interindividual pharmacokinetic (PK) and pharmacodynamic (PD) variability. Unfortunately these methods sometime fail to detect interactions expected on biochemical and/or pharmacological basis and the reasons of these false negatives are somewhat unclear. The aim of this paper is firstly to propose a strategy to detect and assess PD drug-drug interactions when performing the analysis with a nonparametric population approach, then to evaluate the influence of some design variates (i.e., number of subjects, individual measurements) and of the PD interindividual variability level on the performances of the suggested strategy. Two interacting drugs A and B are considered, the drug B being supposed to exhibit by itself a pharmacological action of no interest in this work but increasing the A effect. Concentrations of A and B after concomitant administration are simulated as well as the effect under various combinations of design variates and PD variability levels in the context of a controlled trial. Replications of simulated data are then analyzed by the NPML method, the concentration of the drug B being included as a covariate. In a first step, no model relating the latter to each PD parameter is specified and the NPML results are then proceeded graphically, and also by examining the expected reductions of variance and entropy of the estimated PD parameter distribution provided by the covariate. In a further step, a simple second stage model suggested by the graphic approach is introduced, the fixed effect and its associated variance are estimated and a statistical test is then performed to compare this fixed effect to a given value. The performances of our strategy are also compared to those of a non-population-based approach method commonly used for detecting interactions. Our results illustrate the relevance of our strategy in a case where the concentration of one of the two drugs can be included as a covariate and show that an existing interaction can be detected more often than with a usual approach. The prominent role of the interindividual PD variability level and of the two controlled factors is also shown.

Algorithms↗
PubMed1999

Asymmetries in brain maturation and behavioral disturbances: multivariate electroencephalogram and P300 studies.

If behavior results from brain function, some evidence of dysfunction could be expected in children with major behavioral problems. Yet, neurophysiologic studies in these children are frequently normal. We hypothesized a relationship between maturational asymmetry and behavior, given the role of hemispheric imbalance in adult psychopathology. The purpose of this study was to investigate whether age-sensitive neurophysiologic measures could identify behaviorally relevant maturational asymmetries in otherwise healthy children. Ninety-five children were studied; reasons for testing were behavioral (19), academic (12), medical nonneurologic (16), and mixed (28), along with 20 control subjects. Academic, behavioral (Child Behavioral Checklist), and psychometric (Wechsler Intelligence Scale for Children-Revised; WISC-R) measures were analyzed in relation to four neurophysiologic parameters: P300 Latency, P300 Latency Asymmetry, Maturational Z-score, and Maturational Z-score Asymmetry, within a canonical design. The highest correlation was behavior with Maturational Z-score Asymmetry. Academic scores were predicted by the three-variable interaction of P300 Latency,Maturational Z-score, and Maturational Z-score Asymmetry. We concluded that behavior was strongly influenced by maturational asymmetry, while academic performance depended on both global maturation and maturational asymmetry. Our results suggest that behavioral disturbances can have a neural substrate despite apparently normal electroencephalograms (EEGs) and event-related potentials (ERPs). They open the possibility for specific therapeutic interventions to improve behavior and performance, and, perhaps, prevent major psychopathology in later life.

Achievement↗
PubMed1998

Comparison of four sib-pair linkage methods for analyzing sibships with more than two affecteds: interest of the binomial maximum likelihood approach.

Family samples collected for sib-pair linkage studies usually include some sibships with more than two affecteds (multiplex sibships). Several methods have been proposed to take into account these multiplex sibships, and four of them are discussed in this work. Two methods, which are the most widely used, are based on the number of alleles shared by the sib-pairs constitutive of the multiplex sibship, with the first using the total number of these shared alleles ("all possible pairs" method) and the second considering a weighted number of these alleles (weighted method). The two other approaches considered the sibship as a whole, with in particular a likelihood method based on a binomial distribution of parental alleles among affected offspring. We theoretically show that, in the analysis of sibships with two affecteds, this likelihood method is expected to be more powerful than the classical mean test when a common asymptotic type I error is used. The variation of the sibship informativeness (assessed by the proportion of heterozygous parents) according to the number of affected sibs is investigated under various genetic models. Simulations under the null hypothesis of no linkage indicate that the "all possible pairs" is anticonservative, especially for type I errors < or = 0.001, whereas the weighted method generally provides satisfactory results. The likelihood method shows very consistent results in terms of type I errors, whatever the sample size, and provides power levels similar to those of the other methods. This binomial likelihood approach, which accounts in a natural way for multiplex sibships and provides a simple likelihood-ratio test for linkage involving a single parameter, appears to be a quite interesting alternative to analyze sib-pair studies.

Adult↗