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Biomedical subjects

T Hastie

Publications and source records attributed to T Hastie.

18 recordsLinked to original sources
PubMed2002

Cortisol and behavior in fragile X syndrome.

OBJECTIVE: The purpose of this study was to determine if children with fragile X syndrome, who typically demonstrate a neurobehavioral phenotype that includes social anxiety, withdrawal, and hyper-arousal, have increased levels of cortisol, a hormone associated with stress. The relevance of adrenocortical activity to the fragile X phenotype also was examined. METHOD: One hundred and nine children with the fragile X full mutation (70 males and 39 females) and their unaffected siblings (51 males and 58 females) completed an in-home evaluation including a cognitive assessment and a structured social challenge task. Multiple samples of salivary cortisol were collected throughout the evaluation day and on two typical non-school days. Measures of the fragile X mental retardation (FMR1) gene, child intelligence, the quality of the home environment, parental psychopathology, and the effectiveness of educational and therapeutic services also were collected. Linear mixed-effects analyses were used to examine differences in cortisol associated with the fragile X diagnosis and gender (fixed effects) and to estimate individual subject and familial variation (random effects) in cortisol hormone levels. Hierarchical multiple regression analyses were conducted to determine whether adrenocortical activity is associated with behavior problems after controlling for significant genetic and environmental factors. RESULTS: Results showed that children with fragile X, especially males, had higher levels of salivary cortisol on typical days and during the evaluation. Highly significant family effects on salivary cortisol were detected, consistent with previous work documenting genetic and environmental influences on adrenocortical activity. Increased cortisol was significantly associated with behavior problems in boys and girls with fragile X but not in their unaffected siblings. CONCLUSIONS: These results provide evidence that the function of the hypothalamic-pituitary-adrenal axis may have an independent association with behavioral problems in children with fragile X syndrome.

Adolescent↗
PubMed2001

Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications.

The purpose of this study was to classify breast carcinomas based on variations in gene expression patterns derived from cDNA microarrays and to correlate tumor characteristics to clinical outcome. A total of 85 cDNA microarray experiments representing 78 cancers, three fibroadenomas, and four normal breast tissues were analyzed by hierarchical clustering. As reported previously, the cancers could be classified into a basal epithelial-like group, an ERBB2-overexpressing group and a normal breast-like group based on variations in gene expression. A novel finding was that the previously characterized luminal epithelial/estrogen receptor-positive group could be divided into at least two subgroups, each with a distinctive expression profile. These subtypes proved to be reasonably robust by clustering using two different gene sets: first, a set of 456 cDNA clones previously selected to reflect intrinsic properties of the tumors and, second, a gene set that highly correlated with patient outcome. Survival analyses on a subcohort of patients with locally advanced breast cancer uniformly treated in a prospective study showed significantly different outcomes for the patients belonging to the various groups, including a poor prognosis for the basal-like subtype and a significant difference in outcome for the two estrogen receptor-positive groups.

Algorithms↗
PubMed2001

Supervised harvesting of expression trees.

BACKGROUND: We propose a new method for supervised learning from gene expression data. We call it 'tree harvesting'. This technique starts with a hierarchical clustering of genes, then models the outcome variable as a sum of the average expression profiles of chosen clusters and their products. It can be applied to many different kinds of outcome measures such as censored survival times, or a response falling in two or more classes (for example, cancer classes). The method can discover genes that have strong effects on their own, and genes that interact with other genes. RESULTS: We illustrate the method on data from a lymphoma study, and on a dataset containing samples from eight different cancers. It identified some potentially interesting gene clusters. In simulation studies we found that the procedure may require a large number of experimental samples to successfully discover interactions. CONCLUSIONS: Tree harvesting is a potentially useful tool for exploration of gene expression data and identification of interesting clusters of genes worthy of further investigation.

Gene Expression Profiling↗
PubMed2001

Missing value estimation methods for DNA microarrays.

MOTIVATION: Gene expression microarray experiments can generate data sets with multiple missing expression values. Unfortunately, many algorithms for gene expression analysis require a complete matrix of gene array values as input. For example, methods such as hierarchical clustering and K-means clustering are not robust to missing data, and may lose effectiveness even with a few missing values. Methods for imputing missing data are needed, therefore, to minimize the effect of incomplete data sets on analyses, and to increase the range of data sets to which these algorithms can be applied. In this report, we investigate automated methods for estimating missing data. RESULTS: We present a comparative study of several methods for the estimation of missing values in gene microarray data. We implemented and evaluated three methods: a Singular Value Decomposition (SVD) based method (SVDimpute), weighted K-nearest neighbors (KNNimpute), and row average. We evaluated the methods using a variety of parameter settings and over different real data sets, and assessed the robustness of the imputation methods to the amount of missing data over the range of 1--20% missing values. We show that KNNimpute appears to provide a more robust and sensitive method for missing value estimation than SVDimpute, and both SVDimpute and KNNimpute surpass the commonly used row average method (as well as filling missing values with zeros). We report results of the comparative experiments and provide recommendations and tools for accurate estimation of missing microarray data under a variety of conditions.

Algorithms↗
PubMed2001

Brain anatomy, gender and IQ in children and adolescents with fragile X syndrome.

This study utilized MRI data to describe neuroanatomical morphology in children and adolescents with fragile X syndrome, the most common inherited cause of developmental disability. The syndrome provides a model for understanding how specific genetic factors can influence both neuroanatomy and cognitive capacity. Thirty-seven children and adolescents with fragile X syndrome received an MRI scan and cognitive testing. Scanning procedures and analytical strategies were identical to those reported in an earlier study of 85 typically developing children, permitting a comparison with a previously published template of normal brain development. Regression analyses indicated that there was a normative age-related decrease in grey matter and an increase in white matter. However, caudate and ventricular CSF volumes were significantly enlarged, and caudate volumes decreased with age. Rates of reduction of cortical grey matter were different for males and females. IQ scores were not significantly correlated with volumes of cortical and subcortical grey matter, and these relationships were statistically different from the correlational patterns observed in typically developing children. Children with fragile X syndrome exhibited several typical neurodevelopmental patterns. Aberrations in volumes of subcortical nuclei, gender differences in rates of cortical grey matter reduction and an absence of correlation between grey matter and cognitive performance provided indices of the deleterious effects of the fragile X mutation on the brain's structural organization.

Adolescent↗
PubMed2000

'Gene shaving' as a method for identifying distinct sets of genes with similar expression patterns.

BACKGROUND: Large gene expression studies, such as those conducted using DNA arrays, often provide millions of different pieces of data. To address the problem of analyzing such data, we describe a statistical method, which we have called 'gene shaving'. The method identifies subsets of genes with coherent expression patterns and large variation across conditions. Gene shaving differs from hierarchical clustering and other widely used methods for analyzing gene expression studies in that genes may belong to more than one cluster, and the clustering may be supervised by an outcome measure. The technique can be 'unsupervised', that is, the genes and samples are treated as unlabeled, or partially or fully supervised by using known properties of the genes or samples to assist in finding meaningful groupings. RESULTS: We illustrate the use of the gene shaving method to analyze gene expression measurements made on samples from patients with diffuse large B-cell lymphoma. The method identifies a small cluster of genes whose expression is highly predictive of survival. CONCLUSIONS: The gene shaving method is a potentially useful tool for exploration of gene expression data and identification of interesting clusters of genes worth further investigation.

Algorithms↗
PubMed1999

Meta-analysis of trials comparing beta-blockers, calcium antagonists, and nitrates for stable angina.

CONTEXT: Which drug is most effective as a first-line treatment for stable angina is not known. OBJECTIVE: To compare the relative efficacy and tolerability of treatment with beta-blockers, calcium antagonists, and long-acting nitrates for patients who have stable angina. DATA SOURCES: We identified English-language studies published between 1966 and 1997 by searching the MEDLINE and EMBASE databases and reviewing the bibliographies of identified articles to locate additional relevant studies. STUDY SELECTION: Randomized or crossover studies comparing antianginal drugs from 2 or 3 different classes (beta-blockers, calcium antagonists, and long-acting nitrates) lasting at least 1 week were reviewed. Studies were selected if they reported at least 1 of the following outcomes: cardiac death, myocardial infarction, study withdrawal due to adverse events, angina frequency, nitroglycerin use, or exercise duration. Ninety (63%) of 143 identified studies met the inclusion criteria. DATA EXTRACTION: Two independent reviewers extracted data from selected articles, settling any differences by consensus. Outcome data were extracted a third time by 1 of the investigators. We combined results using odds ratios (ORs) for discrete data and mean differences for continuous data. Studies of calcium antagonists were grouped by duration and type of drug (nifedipine vs nonnifedipine). DATA SYNTHESIS: Rates of cardiac death and myocardial infarction were not significantly different for treatment with beta-blockers vs calcium antagonists (OR, 0.97; 95% confidence interval [CI], 0.67-1.38; P = .79). There were 0.31 (95% CI, 0.00-0.62; P = .05) fewer episodes of angina per week with beta-blockers than with calcium antagonists. beta-Blockers were discontinued because of adverse events less often than were calcium antagonists (OR, 0.72; 95% CI, 0.60-0.86; P<.001). The differences between beta-blockers and calcium antagonists were most striking for nifedipine (OR for adverse events with beta-blockers vs nifedipine, 0.60; 95% CI, 0.47-0.77). Too few trials compared nitrates with calcium antagonists or beta-blockers to draw firm conclusions about relative efficacy. CONCLUSIONS: beta-Blockers provide similar clinical outcomes and are associated with fewer adverse events than calcium antagonists in randomized trials of patients who have stable angina.

Adrenergic beta-Antagonists↗
PubMed1999

Bone mineral acquisition in healthy Asian, Hispanic, black, and Caucasian youth: a longitudinal study.

Ethnic and gender differences in bone mineral acquisition were examined in a longitudinal study of 423 healthy Asian, black, Hispanic, and white males and females (aged 9-25 yr). Bone mass of the spine, femoral neck, total hip, and whole body was measured annually for up to 4 yr by dual energy x-ray absorptiometry. Age-adjusted mean bone mineral curves for areal (BMD) and volumetric (BMAD) bone mineral density were compared for the 4 ethnic groups. Consistent differences in areal and volumetric bone density were observed only between black and nonblack subjects. Among females, blacks had greater mean levels of BMD and BMAD at all skeletal sites. Differences among Asians, Hispanics, and white females were significant for femoral neck BMD, whole body BMD, and whole body bone mineral content/height ratio, for which Asians had significantly lower values; femoral neck BMAD in Asian and white females was lower than that in Hispanics. Like the females, black males had consistently greater mean values than nonblacks for all BMD and BMAD measurements. A few differences were also observed among nonblack male subjects. Whites had greater mean total hip BMD, whole body BMD, and whole body bone mineral content/height ratio than Asian and Hispanic males; Hispanics had lower spine BMD than white and Asian males. The tempo of gains in BMD varied by gender and skeletal site. In females, total hip, spine, and whole body BMD reached a plateau at 14.1, 15.7, and 16.4 yr, respectively. For males, gains in BMD leveled off at 15.7 yr for total hip and at age 17.6 yr for spine and whole body. Black and Asian females and Asian males tended to reach a plateau in BMD earlier than the other ethnic groups. The use of gender- and ethnic-specific standards is recommended when interpreting pediatric bone densitometry data.

Absorptiometry, Photon↗
PubMed1998

Regression analysis of multiple protein structures.

A general framework is presented for analyzing multiple protein structures using statistical regression methods. The regression approach can superimpose protein structures rigidly or with shear. Also, this approach can superimpose multiple structures explicitly, without resorting to pairwise superpositions. The algorithm alternates between matching corresponding landmarks among the protein structures and superimposing these landmarks. Matching is performed using a robust dynamic programming technique that uses gap penalties that adapt to the given data. Superposition is performed using either orthogonal transformations, which impose the rigid-body assumption, or affine transformations, which allow shear. The resulting regression model of a protein family measures the amount of structural variability at each landmark. A variation of our algorithm permits a separate weight for each landmark, thereby allowing one to emphasize particular segments of a protein structure or to compensate for variances that differ at various positions in a structure. In addition, a method is introduced for finding an initial correspondence, by measuring the discrete curvature along each protein backbone. Discrete curvature also characterizes the secondary structure of a protein backbone, distinguishing among helical, strand, and loop regions. An example is presented involving a set of seven globin structures. Regression analysis, using both affine and orthogonal transformations, reveals that globins are most strongly conserved structurally in helical regions, particularly in the mid-regions of the E, F, and G helices.

Algorithms↗
PubMed1998

Modeling and superposition of multiple protein structures using affine transformations: analysis of the globins.

A novel approach for analyzing multiple protein structures is presented. A family of related protein structures may be characterized by an affine model, obtained by applying transformation matrices that permit both rotation and shear. The affine model and transformation matrices can be computed efficiently using a single eigen-decomposition. A novel method for finding correspondences is also introduced. This method matches curvatures along the protein backbone. The algorithm is applied to analyze a set of seven globin structures. Our method identifies 100 corresponding landmarks across all seven structures. Results show that most helices in globins can be identified by high curvature, with the exception of the C and D helices. Analysis of the superposition reveals that globins are most strongly conserved structurally in the mid-regions of the E and G helices.

Algorithms↗
PubMed1995

Generalized additive models for medical research.

This article reviews flexible statistical methods that are useful for characterizing the effect of potential prognostic factors on disease endpoints. Applications to survival models and binary outcome models are illustrated.

Algorithms↗
PubMed1992

Flexible covariate effects in the proportional hazards model.

The proportional hazards model is frequently used in analyzing the results of clinical trials, when it is often the case that the outcomes are right-censored. This model allows one to measure treatment effects and simultaneously identify and adjust for prognostic factors that might influence the outcome. In this paper, we outline a class of semiparametric models that allows one to model prognostic factors nonlinearly, and have the data suggest the form of their effect. The methods are illustrated in an analysis of data from a breast cancer clinical trial.

Adult↗
PubMed1990

Exploring the nature of covariate effects in the proportional hazards model.

We discuss an exploratory technique for investigating the nature of covariate effects in Cox's proportional hazards model. This technique features an additive term sigma p1 fj(chi ij), in place of the usual linear term sigma p1 chi ij beta j, where chi i1, chi i2,...,chi ip are covariate values for the ith individual. The fj(.) are unspecified smooth functions that are estimated using scatterplot smoothers. These functions can be used for descriptive purposes or to suggest transformations of the covariates. The estimation technique is a variation of the local scoring algorithm for generalized additive models (Hastie and Tibshirani, 1986, Statistical Science 1, 297-318).

Algorithms↗
PubMed1982

Closed mitral valvotomy: actuarial analysis of results in 654 patients over 12 years and analysis of preoperative predictors of long-term survival.

The records of 654 patients with mitral stenosis who underwent closed mitral valvotomy over a 12-year period were submitted to actuarial analysis. This revealed a low (2.97%) operative mortality. At 12 years, the overall cumulative proportion surviving was 78%; 47% of patients survived without reoperation. The usual clinical indicators of suitability for closed valvotomy were successful in predicting improved survival. The surgeon's assessment of the suitability of the valve correlated well with outcome. Valvotomy during pregnancy was associated with a good long-term outlook. The presence of pulmonary hypertension and atrial fibrillation did not alter survival significantly. Sex ane age were not associated with adverse prognosis. We conclude that closed mitral valvotomy still has a place in the management of mobile mitral stenosis, particularly in areas where there is a high incidence of rheumatic heart disease and a large number of young patients have mobile mitral stenosis.

Actuarial Analysis↗
PubMed1979

Risk of asbestosis in crocidolite and amosite mines in South Africa.

X-rays of all while and mixed-race men employed in crocidolite and amosite mines and mills were read independently by three experienced readers according to the ILO U/C classification. Abnormality was regarded as present if reported by two or more readers. Parenchymal abnormality, defined as the presence of small irregular opacities of profusion 1/0 or greater, was found in 7.3% of the workers. Pleural thickening was found in 4.5% of the workers, costophrenic angle obliteration in 3.2%, and pleural calcification in 1.7%. The prevalences of both pleural and parenchymal abnormality were strongly related to the duration of exposure to asbestos at work. The overall prevalence of abnormality increase from 4.0% in men with exposure for 1 year or less to 47.9% in men with more than 15 years of exposure. After taking into account the effects of age and duration of asbestos exposure, the prevalence of pleural abnormality was not predicted by fiber concentration. However, white men working with amosite tended to develop a higher prevalence of pleural abnormality than did those working with crocidolite. Compared to whites, men of mixed race, who only work with crocidolite, had a high prevalence of pleural abnormality in each exposure duration category. In contrast to pleural abnormality, the prevalence of parenchymal abnormality, after taking into account the effects of age and duration of exposure, was significantly predicted by fiber concentration but not by race or asbestos type. Our results suggest that parenchymal abnormality in workers in South African asbestos mines could be largely prevented by reducing exposure to fibers visible under the light microscope. However, this may not be the case for pleural abnormality.

Adult↗