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PubMed1985

Evidence of bimodality of two hour plasma glucose concentrations in Mexican Americans: results from the San Antonio Heart study.

Evidence for bimodality in the distribution of two hour post oral glucose challenge plasma glucose concentrations has come previously primarily from native American and Pacific Island populations having high non-insulin dependent diabetes mellitus (NIDDM) prevalence. Because the National Diabetes Data Group (NDDG) criteria for diagnosing NIDDM rely in part upon the assumption of bimodality, it is important to determine the generality of this phenomenon. We looked for bimodality among Mexican Americans in San Antonio, a population having greater than 50% Caucasian admixture. By fitting both a single normal distribution model and a mixture model of two normal distributions, for each age decade, we found that the mixture model was preferred to the single normal model (p less than 0.001) and that this model fit the data well. The proportion in the upper component (hyperglycemics) increased with each successive age decade. The minimum misclassification cutpoints decreased with age, but all were higher than the 200 mg/dl cutpoint recommended by the NDDG. Use of the NDDG cutpoint, however, improved sensitivity with only a minimal deterioration of specificity. Our findings further generalize the bimodality phenomenon and support the NDDG criteria.

Adult↗

PubMed2004

CYP1A2 in a smoking and a non-smoking population; correlation of urinary and salivary phenotypic ratios.

The use of caffeine as a probe for CYP1A2 phenotyping has been extensively investigated over the last 25 years. Numerous metabolic ratios have been employed and various biological fluids analysed for caffeine and its metabolites. These investigations have used non-smoking, smoking and numerous disease populations to investigate the role of CYP1A2 in possible disease aetiology and for induction and inhibition studies in vivo using dietary, environmental and pharmaceutical compounds. This investigation found that the 17X/137X CYP1A2 metabolic ratio in a 5 h saliva sample and 0-5 h urine collection was not normally distributed in both a non-smoking and a smoking population. The urinary and salivary CYP1A2 metabolic ratio was log normally distributed in the non-smoking population but the smoking population showed a bi- (or tri-)modal distribution on log transformation of both the urinary and salivary CYP1A2 metabolic ratios. The CYP1A2 metabolic ratios were significantly higher in the smoking population compared to the non-smoking population when both the urinary and salivary CYP1A2 metabolic ratios were analysed. These results indicate that urinary flow rate was not a factor in the variation in CYP1A2 phenotype in the non-smoking and smoking populations studied here. The increased CYP1A2 activity in the smoking population was probably due to induction of the CYP1A2 gene via the Ah receptor causing an increase in the concentration of CYP1A2 protein.

Adolescent↗

PubMed1977

The size of growth hormone granules in pituitary adenomas producing acromegaly.

Measurements of the diameters of large numbers of granules in electron micrographs of pituitary adenomas in cases of acromegaly do not show that a typical size exists which allows of the retrospective diagnosis of the hormone secreted by the tumour. The granule diameters found in single cases show a normal distribution. The average values determined in 19 unselected cases of acromegaly range between 160 and 342 nm. They are also normally distributed about the mean for the entire group which is 238 nm. With histo-immunological electron microscopic techniques h GH can be demonstrated in small, medium and large granules. The size of hormone granules is determined by functional factors such as the speed of hormone synthesis and hormone release but not by the type of hormone secreted.

Acromegaly↗

PubMed2005

Refractive error and ocular biometry in Jordanian adults.

The aim of this study was to establish the prevalence of refractive errors in Jordanian adults of working age, and to study the ocular biometric correlates of refractive error in this population. Refractive error and ocular biometry were measured in 1093 Jordanian adult subjects aged 17-40 years to determine the prevalence of refractive error, and explore structural correlations of ametropia. Refractive error was measured using a Grand-Seiko GR-3100K closed-view infrared autorefractor. Ocular component measurements were made using A-scan ultrasonography and autokeratometry. The prevalence of myopia [spherical equivalent refraction (SER) less than -0.50 DS] and hyperopia (SER greater than +0.50 DS) was 53.71 and 5.67% respectively; 40.62% of the sample was emmetropic (refraction between +0.50 D and -0.50 D inclusive in both principal meridians). The distribution of SER was found to show marked leptokurtosis, exhibiting a peak between plano and 1 D of myopia. Corneal radius, anterior chamber depth, crystalline lens thickness, vitreous chamber depth and axial length (AL) parameters were normally distributed in the population studied. AL to corneal curvature ratio was not normally distributed, and showed marked leptokurtosis. Linear regression analysis showed that AL correlated most closely with spherical equivalent refractive error. This study has established a database of refractive error prevalence and ocular biometric correlates of ametropia in a Middle Eastern population of working age.

Adolescent↗

PubMed1998

A Markov mixed effect regression model for drug compliance.

Patient compliance (adherence) with prescribed medication is often erratic, while clinical outcomes are causally linked to actual, rather than nominal medication dosage. We propose here a hierarchical Markov model for patient compliance. At the first stage, conditional upon individual random effects and a set of individual-specific nominal daily dose times, we assume that (i) the subject-specific probability of taking zero, one, or more than one dose associated with a given nominal dose time depends on the value of certain covariates, and on the number of doses associated with the immediate previous time, but is independent of any other previous or future dosing events (the Markov hypothesis); and (ii) the set of 'errors' between actual dose times associated with each nominal time is multivariate normally distributed, conditional on covariates and the number of such actual dose times, as in (i). At the second stage, a multivariate normal distribution is assumed for the individual random effects. We fit this model by maximum likelihood to data collected over three months using an electronic system for recording actual dose times in HIV-positive patients assigned to a regimen of zidovudine thrice daily. Beyond its value for describing and quantifying compliance behaviour, as illustrated here, the model may prove useful for explanatory analyses of clinical trials.

Anti-HIV Agents↗

PubMed2004

Arsenic and other elements in hair, nails, and skin-scales of arsenic victims in West Bengal, India.

For the first time, biological tissues (hair, nails, and skin-scales) of arsenic victims from an arsenic affected area of West Bengal (WB), India were analyzed for trace elements. Analysis was carried out by inductively coupled plasma-mass spectrometry (ICP-MS) for 10 elements (As, Se, Hg, Zn, Pb, Ni, Cd, Mn, Cu, and Fe). A microwave digester was used for digestion of the tissue samples. To validate the method, certified reference materials--human hair (GBW 07601) and bovine muscle (CRM 8414)--were analyzed for all elements. The W test was used to study the normal/log normal distribution for each element in the tissue samples. For hair (n=44) and nails (n=33), all elements show log-normal distribution. For skin-scale samples (n=11), data are not sufficient to provide the information about the trend. Geometric mean, standard error, and range for each element were presented and compared with literature values for other populations. This study reveals the higher levels of toxic elements As, Mn, Pb, and Ni in the tissue samples compared with available values in the literature. The elevated levels of these toxic metals in the tissues may be due to exposure of these elements through drinking water and food. The correlations of Mn and Ni with other essential elements, e.g. Fe, Cu, Zn, suggest that Mn and Ni may substitute for those elements in hair, nails, and skin-scales. However, correlation represents the relation between two elements only and does not take into consideration of the presence of other elements. Principle component analysis was applied to explain the behavior among the elements present in hair and nails. This study reveals that in the arsenic-affected areas of WB, the concentrations of other toxic elements in drinking water and foodstuff should be monitored to evaluate the arsenic poisoning.

Arsenic↗

PubMed2004

Mapping QTLs for traits measured as percentages.

Many quantitative traits are measured as percentages. As a result, the assumption of a normal distribution for the residual errors of such percentage data is often violated. However, most quantitative trait locus (QTL) mapping procedures assume normality of the residuals. Therefore, proper data transformation is often recommended before statistical analysis is conducted. We propose the probit transformation to convert percentage data into variables with a normal distribution. The advantage of the probit transformation is that it can handle measurement errors with heterogeneous variance and correlation structure in a statistically sound manner. We compared the results of this data transformation with other transformations and found that this method can substantially increase the statistical power of QTL detection. We develop the QTL mapping procedure based on the maximum likelihood methodology implemented via the expectation-maximization algorithm. The efficacy of the new method is demonstrated using Monte Carlo simulation.

Chromosome Mapping↗

PubMed2003

The quantitative assessment of body iron.

Current initiatives to reduce the high prevalence of nutritional iron deficiency have highlighted the need for reliable epidemiologic methods to assess iron status. The present report describes a method for estimating body iron based on the ratio of the serum transferrin receptor to serum ferritin. Analysis showed a single normal distribution of body iron stores in US men aged 20 to 65 years (mean +/- 1 SD, 9.82 +/- 2.82 mg/kg). A single normal distribution was also observed in pregnant Jamaican women (mean +/- 1 SD, 0.09 +/- 4.48 mg/kg). Distribution analysis in US women aged 20 to 45 years indicated 2 populations; 93% of women had body iron stores averaging 5.5 +/- 3.35 mg/kg (mean +/- 1 SD), whereas the remaining 7% of women had a mean tissue iron deficit of 3.87 +/- 3.23 mg/kg. Calculations of body iron in trials of iron supplementation in Jamaica and iron fortification in Vietnam demonstrated that the method can be used to calculate absorption of the added iron. Quantitative estimates of body iron greatly enhance the evaluation of iron status and the sensitivity of iron intervention trials in populations in which inflammation is uncommon or has been excluded by laboratory screening. The method is useful clinically for monitoring iron status in those who are highly susceptible to iron deficiency.

Adult↗

PubMed1998

Random noise in the spectra of evoked otoacoustic emissions.

Noise from the measuring equipment and from environmental and physiological sources is inevitably present in records of evoked otoacoustic emissions. This paper considers the influence of noise on the power spectra of otoacoustic emissions as recorded with the Otodynamics ILO88 system. It is shown that if the noise has a normal distribution, the ratio of the power in the response spectrum to the power in the noise has an approximately log-normal distribution. It is also shown that the change in the level of the response spectrum that is observed when measurements are repeated is related through a t-distribution to the estimate of the noise-to-signal ratio that these measurements provide. The statistical analysis leads to simple significance tests that may be helpful in detecting the presence of an emission and that allow small changes in the spectrum to be identified.

Acoustic Stimulation↗

PubMed2000

[Somatic development of asthmatic children and youth].

UNLABELLED: Systemic diseases especially the chronic ones, causing substance and oxygen insufficiency may lead to disturbances in growth, in the nutritional status and slowing of the maturation processes. Bronchial asthma is the most frequent inflammatory chronic disease of the respiratory system and it is estimated, that 5-10% of the population in the development period suffers from it. Somatic development retardation, disturbances in the nutritional status and maturation may be caused by respiratory insufficiency leading to anoxia, improper nutritional habits, recurrent or chronic infections, long-term physical and mental stress, limited physical activity and also pharmacological therapy. THE AIM of this work was to conduct, in children with bronchial asthma, the evaluation of: somatic development, body proportions, nutritional status, sexual maturation depending on the duration and degree of severity of the disease. The second aim was to assess whether the assumed standard for complex treatment depending on the severity of the diseases may lead to normal somatic development. MATERIAL: In the research comprised 508 children (3 1 5 boys and 93 girls) between 7 and 1 5 years of age, treated for bronchial asthma in the Paediatric Department of the Institute of Tuberculosis and Lung Diseases in Rabka. Due to the multiplicity of factors influencing the course of development, the following were observed in the studied groups: birth weight and length, average height of parents (selected genetic factors); place of domicile and educational level of the parents (social-economic factors). The study concerned children born with normal birth weight and length. Evaluation of the impact of genetic factors, was based on the analysis of parent's height; it did not differ in the studied groups with regard to the women's or men's height in the average population. The majority of the studied children lived in towns, every third child lived in the country. Parents of the studied children suffering from asthma had a higher educational level than the Polish population. METHODS: The level of somatic development and body proportions were evaluated with reference to direct anthropometric measurements: body height and weight, head and chest circumference, length of trunk, width of shoulders and hips, width and depth of the chest, and indexes of the trunk length, shoulder-hip and chest. The nutritional status was evaluated by the following anthropometric measurements, according to WHO/FAO recommendations: circumference of the arm and thigh, subscapular and abdominal skinfold thickness, BMI and the arm muscle circumference, according to Frisancho. All the above anthropometric measurements and indices were analyzed in groups of children depending on the severity and duration of the disease (classification according to the Global Strategy for Asthma Management and Prevention NHLBI/WHO, NIH Publication, 1998) group I -- episodic and mild asthma (I and II degree) duration up to 3 years, group II -- moderate and severe asthma (III and IV degree) duration up to 3 years, group III -- episodic and mild asthma (I and II degree) duration over 3 years group IV -- moderate and severe asthma (III and IV degree) duration over 3 years. The obtained results were compared with data for healthy Warsaw population. In order to compare the level and variation of different somatic measurements and indices in children at different ages measurement results were transformed to standard normal distribution with a mean of 0 and standard deviation of 1. Moreover, in order to evaluate the variation of features with normal distribution within the groups and between the studied groups, analysis of variance ANOVA was used (acc. to the STATISTICA programme). This enabled the comparison of anthropometric measurements and indices in children with bronchial asthma in the four studied groups. To determine the statistical significance between the arithmetical means of the studied features in children with bronchial asthma and in healthy children, the t-Student test for independent samples was applied. These differences between selected groups depending on the degree of severity of the disease and its duration and between the four groups, based on the severity of the disease and its duration, on one hand and healthy children on the other were evaluated. The features and anthropometric indexes with naturally skewed distribution of measurement results were evaluated using centile values and medians. The subscapular and abdominal skinfold thickness after calculating centile values, were estimated on centile charts for this feature in the Warsaw population. The value of the skinfold thickness in centile intervals in isolated groups depending on severity of the illness and its duration and in the four groups, considering severity and duration of illness, was also analyzed. (ABSTRACT TRUNCATED)

Adolescent↗

PubMed2005

Bootstrap resampling method to estimate confidence intervals of activation-induced CBF changes using laser Doppler imaging.

Laser Doppler imaging (LDI) signal and noise characteristics can vary significantly depending upon the underlying vascular caliber. Further, noise characteristics are not constant over time (non-stationary) and can vary during resting and activated conditions in a typical experiment. Since only a limited number of images can be acquired in a single run, concatenation of data from similar experimental trials becomes necessary which can induce further variation in temporal noise due to instrumental response. In conventional statistical analysis methods such as cross-correlation, a fixed significance threshold is generally used (for the entire image) to detect activation assuming constant noise over time and a normal distribution. As a consequence, statistical significance can become strong or weak due to temporal differences in baseline LD noise, which can possibly deviate from a normal distribution. The main emphasis of this study was the application of bootstrap resampling in conjunction with cross-correlation to estimate the confidence intervals on a pixel-by-pixel basis to avoid distributional specifications on the additive measurement error leading to reliable whisker activation-induced CBF changes. At a 95% confidence level, bootstrap resampling followed by confidence intervals for the correlation coefficient distribution increased the number of active pixels by almost 45% when compared to conventional cross-correlation. These pixels were mostly confined to areas with intermediate and large baseline LD flux with considerable deviation from normality. It is suggested that confidence intervals of the bootstrap estimates can lead to unbiased detection of CBF change in the cerebral cortex, particularly in regions with large temporal variation in noise and low CNR.

Afferent Pathways↗

PubMed2002

Vertebral scalloping in neurofibromatosis type 1: a quantitative approach.

OBJECTIVE: To investigate quantitative differences in vertebral scalloping between children who have scoliosis with and without neurofibromatosis type 1 (NF1). DESIGN: A retrospective study. SETTING: A university-affiliated children's hospital. PATIENTS: Twenty-seven children with scoliosis, 13 of whom had NF1 and 14 of whom did not. METHOD: Existing radiographs of the lumbar vertebrae were used to measure and compare the degree of vertebral scalloping. MAIN OUTCOME MEASURES: The distribution of posterior scalloping ratios in the 2 groups and the most extreme ratio in each subject in each group were compared. RESULTS: Scalloping ratios from the children with NF1 were not normally distributed: 31% had ratios greater than 1.20. Scalloping ratios from the non-NF1 children were normally distributed, with a mean ratio (and standard deviation) of 1.13 (0.03). The distribution between the 2 groups was significantly different (p < 0.05). CONCLUSIONS: In children who have scoliosis but no NF1 there was a range of mild scalloping whereas those with NF1 has severe scalloping. Further studies are needed to determine the possible role of vertebral scalloping in scoliosis severity and progression in children who have NF1.

Adolescent↗

PubMed1999

Classifier design for computer-aided diagnosis: effects of finite sample size on the mean performance of classical and neural network classifiers.

Classifier design is one of the key steps in the development of computer-aided diagnosis (CAD) algorithms. A classifier is designed with case samples drawn from the patient population. Generally, the sample size available for classifier design is limited, which introduces variance and bias into the performance of the trained classifier, relative to that obtained with an infinite sample size. For CAD applications, a commonly used performance index for a classifier is the area, Az, under the receiver operating characteristic (ROC) curve. We have conducted a computer simulation study to investigate the dependence of the mean performance, in terms of Az, on design sample size for a linear discriminant and two nonlinear classifiers, the quadratic discriminant and the backpropagation neural network (ANN). The performances of the classifiers were compared for four types of class distributions that have specific properties: multivariate normal distributions with equal covariance matrices and unequal means, unequal covariance matrices and unequal means, and unequal covariance matrices and equal means, and a feature space where the two classes were uniformly distributed in disjoint checkerboard regions. We evaluated the performances of the classifiers in feature spaces of dimensionality ranging from 3 to 15, and design sample sizes from 20 to 800 per class. The dependence of the resubstitution and hold-out performance on design (training) sample size (Nt) was investigated. For multivariate normal class distributions with equal covariance matrices, the linear discriminant is the optimal classifier. It was found that its Az-versus-1/Nt curves can be closely approximated by linear dependences over the range of sample sizes studied. In the feature spaces with unequal covariance matrices where the quadratic discriminant is optimal, the linear discriminant is inferior to the quadratic discriminant or the ANN when the design sample size is large. However, when the design sample is small, a relatively simple classifier, such as the linear discriminant or an ANN with very few hidden nodes, may be preferred because performance bias increases with the complexity of the classifier. In the regime where the classifier performance is dominated by the 1/Nt term, the performance in the limit of infinite sample size can be estimated as the intercept (1/Nt= 0) of a linear regression of Az versus 1/Nt. The understanding of the performance of the classifiers under the constraint of a finite design sample size is expected to facilitate the selection of a proper classifier for a given classification task and the design of an efficient resampling scheme.

Computer Simulation↗

PubMed2006

An adaptive hierarchical test procedure for selecting safe and efficient treatments.

We consider the situation where during a multiple treatment (dose) control comparison high doses are truncated because of lack of safety and low doses are truncated because of lack of efficacy, e.g., by decisions of a data safety monitoring committee in multiple interim looks. We investigate the properties of a hierarchical test procedure for the efficacy outcome in the set of doses carried on until the end of the trial, starting with the highest selected dose group to be compared with the placebo at the full level alpha. Left truncation, i.e., dropping doses in a sequence starting with the lowest dose, does not inflate the type I error rate. It is shown that right truncation does not inflate the type I error if efficacy and toxicity are positively related and dose selection is based on monotone functions of the safety data. A positive relation is given e.g. in the case where the efficacy and toxicity data are normally distributed with a positive pairwise correlation. A positive relation also applies if the probability for an adverse event is increasing with a normally distributed efficacy outcome. The properties of such truncation procedures are investigated by simulations. There is a conflict between achieving a small number of unsafely treated patients and a high power to detect safe and efficient doses. We also investigated a procedure to increase power where a reallocation of the sample size to the truncated treatments and the control remaining at the following stages is performed.

Biometry↗

PubMed2006

Infectious agents, inflammation, and growth factors: how do they interact in the progression or stabilization of mild human atherosclerotic lesions?

Advanced complicated atherosclerotic lesions have been related to many factors, including inflammation, infectious agents, and growth factors. Mycoplasma pneumoniae (MP) and Chlamydia pneumoniae (CP), inflammation, and growth factors have been associated with severe atherosclerotic lesions in necropsy material in recent work at our lab. The present study intends to clarify the pathogenesis of atherosclerosis, analyzing which of these elements (macrophages, MP, CP, lymphocytes, and growth factors) are associated with initial development of atherosclerotic lesions, discriminating elements related to stabilization of the plaque versus those related to subendothelial active accumulation of macrophages in living patients. Surgical ascending aorta fragments presenting mild atherosclerotic lesions from 30 coronary atherosclerotic patients were immunohistochemically quantified regarding CP, MP, T cells (CD4, CD8), B cells (CD20), macrophages (CD68), and growth factors [platelet-derived growth factor A (PDGF-A), PDGF-B, transforming growth factor-beta (TGF-beta), granulocyte-macrophage colony-stimulating factor (GM-CSF)]. Cases were grouped according to the presence or not of active accumulation of macrophages at the subendothelium that indicates atheroma in development: group I (GI) fragments with <4 CD68+ cells/x400 field, in normal distribution (mean 1.8 +/- 1) representing stable atherosclerotic mild lesion, and GII fragments presenting >or=4 CD68+ cells/x400 field, in a non-normal distribution, mean (8.9 +/- 4.8, atheromas in progress), which was followed by increased number of lymphocytes. The median number in GI was significantly lower than that in GII: CD4 T (2.5 vs. 7.7), CD8 T (1.0 vs. 5.5), and CD20 B (1.5 vs. 5.5) cells/x400 field, p < 0.001. Percentage area positive for CP antigens was significantly lower in GI than in GII: 1.0 vs. 9.2, p < 0.001. There was a higher percentage area occupied by MP than CP in both GI and GII (7.8 vs. 13.8). There was no difference regarding mean number of growth factor-positive cells/x400 field: PDGF-A, 1.4 vs. 3.9; PDGF-B, 3.4 vs. 5.7; TGF-beta, 0.9 vs. 2.2; and GM-CSF, 2.0 vs. 2.2. Considering all cases, a positive correlation was seen between inflammatory cells and CP+ cells (r > 0.5 and p < 0.01). Growth factors did not correlate with inflammatory cells, CP, or MP and were usually seen in smooth muscle cell and fibrotic areas. Study of initial atherosclerotic lesions showed that MP is present in both kinds of lesion: stable and active subendothelial accumulation of macrophages. Stabilization was related to proportional increase of both infectious agents, which were also related to increased amount of PDGF-A and PDGF-B. Active macrophage accumulation lesions were related to higher elevation in CP concentration at subendothelial regions, in association with B cells, but not of MP and growth factors. MP and CP, inflammation, and growth factors, which were already described in severe atherosclerotic lesions in necropsy material, are also present in mild lesions in living patients, strongly favoring a pathogenetic role for these bacteria in the pathogenesis of atherosclerosis. Predominance of CP in relation to MP may favor progression of the plaque, which is associated with increased B-cell proliferation. PDGF-A and PDGF-B are associated with plaque stability, at least in arterial segments not prone for development of complicated lesions.

Adult↗

PubMed1976

The study of (Methyl-3H)decamethonium dichloride incorporation into normal and dystrophic mouse muscle.

1. (Methyl-3H)decamethonium dichloride was injected intravenously into the tail vein of dystrophic and normal mice of the Bar Harbour strain 129 ReJ/dy in paralysing doses. 2. Scintillation counts were made of 1 mm sections of diaphragm and tibialis anterior which showed a normal distribution of tritiated decamethonium in the dystrophic animals. 3. Intraperitoneal injections of L-(gamma-3H)leucine were made into dystrophic and normal mice. Examination of diaphragm and tibialis anterior by scintillation counting showed the abnormal uptake typical of dystrophic involvement of murine muscle. 4. The normal distribution of (methyl-3H)decamethonium dichloride uptake by the dystrophic muscle does not support the concept of active denervation in this disease.

Animals↗

PubMedDate not supplied

Prediction of muscle force involved in shoulder internal rotation.

The estimation of shoulder muscle force is important to understand the mechanism of rotator cuff injury. In general, mean parameter values are used as input for computational models. However, anatomic and biomechanical parameters vary widely among people. The purpose of this study was to evaluate shoulder muscle forces predicted by an electromyography-driven muscle model given neuromuscular parameters generated by Monte Carlo simulation. Normal distributions were used to model muscle moment arms; electromyographic and muscle physiological cross-sectional area data were modeled with log-normal distributions. Eight muscles were included in the model. Muscle force and joint moment were predicted on the basis of the simulated parameters. The results showed that the subscapularis and pectoralis major were substantial actuators for shoulder internal rotation. During maximum voluntary contraction the median of the muscle forces of the subscapularis and the pectoralis major were 1030 N and 462 N, respectively. This study demonstrated that the Monte Carlo method could be used for muscle force prediction by integrating population variability of physiological parameter into a biomechanical muscle model.

Biomechanical Phenomena↗

PubMed2002

A unified framework for transmission-disequilibrium test analysis of discrete and continuous traits.

This paper presents a unified framework for transmission-disequilibrium tests for discrete and continuous traits. A conditional score test is derived that maximizes power to detect small effects for any exponential family distribution, which includes binary and normal distributions, and distributions that are skewed or have non-normal kurtosis. The specific distributional form need not be specified, and the method applies to sibships of arbitrary size. Formulas for the distribution of the test statistic are given for models including complex genetic effects (additive, dominant, and recessive gene action), covariates, multiple gene models including gene-gene interactions or heterogeneity, and gene-environment interactions. We develop refinements of our method for trait-based sampling designs and multiple siblings that can have dramatic effects on power.

Alleles↗