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Biomedical subjects

I S Kohane

Publications and source records attributed to I S Kohane.

At least 19 recordsLinked to original sources
PubMed2004

Side population cells isolated from different tissues share transcriptome signatures and express tissue-specific markers.

Side Population (SP) cells, isolated from murine adult bone marrow (BM) based on the exclusion of the DNA dye Hoechst 33342, exhibit potent hematopoietic stem cell (HSC) activity when compared to Main Population (MP) cells. Furthermore, SP cells derived from murine skeletal muscle exhibit both hematopoietic and myogenic potential in vivo. The multipotential capacity of SP cells isolated from variable tissues is supported by an increasing number of studies. To investigate whether the SP phenotype is associated with a unique transcriptional profile, we characterized gene expression of SP cells isolated from two biologically distinct tissues, bone marrow and muscle. Comparison of SP cells with differentiated MP cells within a tissue revealed that SP cells are in an active transcriptional and translational status and underexpress genes reflecting tissue-specific functions. Direct comparison of gene expression of SP cells isolated from different tissues identified genes common to SP cells as well as genes specific to SP cells within a particular tissue and further define a muscle and bone marrow environment. This study reports gene expression of muscle SP cells, common features and differences between SP cells isolated from muscle and bone marrow, and further identifies common signaling pathways that might regulate SP cell functions.

Animals↗
PubMed2002

Molecular profiles of inflammatory myopathies.

OBJECTIVE: To describe the use of large-scale gene expression profiles to distinguish broad categories of myopathy and subtypes of inflammatory myopathies (IM) and to provide insight into the pathogenesis of inclusion body myositis (IBM), polymyositis, and dermatomyositis. METHODS: Using Affymetrix GeneChip microarrays, the authors measured the simultaneous expression of approximately 10,000 genes in muscle specimens from 45 patients in four major disease categories (dystrophy, congenital myopathy, inflammatory myopathy, and normal). The authors separately analyzed gene expression in 14 patients limited to the three major subtypes of IM. Bioinformatics techniques were used to classify specimens with similar expression profiles based on global patterns of gene expression and to identify genes with significant differential gene expression compared with normal. RESULTS: Ten of 11 patients with IM, all normals and nemaline myopathies, and 10 of 12 patients with Duchenne muscular dystrophy were correctly classified by this approach. The various subtypes of inflammatory myopathies have distinct gene expression signatures. Specific sets of immune-related genes allow for molecular classification of patients with IBM, polymyositis, and dermatomyositis. Analysis of differential gene expression identifies as relevant to disease pathogenesis previously reported cytokines, major histocompatibility complex class I and II molecules, granzymes, and adhesion molecules, as well as newly identified members of these categories. Increased expression of actin cytoskeleton genes is also identified. CONCLUSIONS: The molecular profiles of muscle tissue in patients with inflammatory myopathies are distinct and represent molecular signatures from which diagnostic insight may follow. Large numbers of differentially expressed genes are rapidly identified.

Adolescent↗
PubMed2002

SNPper: retrieval and analysis of human SNPs.

MOTIVATION: Single Nucleotide Polymorphisms (SNPs) are an increasingly important tool for the study of the human genome. SNPs can be used as markers to create high-density genetic maps, as causal candidates for diseases, or to reconstruct the history of our genome. SNP-based studies rely on the availability of large numbers of validated, high-frequency SNPs whose position on the chromosomes is known with precision. Although large collections of SNPs exist in public databases, researchers need tools to effectively retrieve and manipulate them. RESULTS: We describe the implementation and usage of SNPper, a web-based application to automate the tasks of extracting SNPs from public databases, analyzing them and exporting them in formats suitable for subsequent use. Our application is oriented toward the needs of candidate-gene, whole-genome and fine-mapping studies, and provides several flexible ways to present and export the data. The application has been publicly available for over a year, and has received positive user feedback and high usage levels.

Database Management Systems↗
PubMed2002

CHIP TUNER: a web tool for evidence-based noise reduction in gene discovery.

The potential for gene discovery, fueled by DNA microchip technology and the sequencing of hundreds of genomes, is unprecedented. In this context, trying to discover genes that are actually of significance rather than merely appearing so due to noise is of utmost importance. We present a web application, CHIP TUNER, which assists in this gene discovery process. Our system uses evidence-based noise reduction to help delineate candidate target genes of biological importance. Specifically, CHIP TUNER learns from redundant experiments an "identity mask" that defines a region of noise inherent to biological sampling and DNA microarray processing; it then takes this into account during actual sample comparisons. The goal of CHIP TUNER is to improve the chances that newly discovered "important" genes are actually of importance before large amounts of time and resources are invested.

Computational Biology↗
PubMed2001

Extracting knowledge from dynamics in gene expression.

Most investigations of coordinated gene expression have focused on identifying correlated expression patterns between genes by examining their normalized static expression levels. In this study, we focus on the dynamics of gene expression by seeking to identify correlated patterns of changes in genetic expression level. In doing so, we build upon methods developed in clinical informatics to detect temporal trends of laboratory and other clinical data. We construct relevance networks from Saccharomyces cerevisiae gene-expression dynamics data and find genes with related functional annotations grouped together. While some of these associations are also found using a standard expression level analysis, many are identified exclusively through the dynamic analysis. These results strongly suggest that the analysis of gene expression dynamics is a necessary and important tool for studying regulatory and other functional relationships among genes. The source code developed for this investigation is freely available to all non-commercial investigators by contacting the authors.

Cluster Analysis↗
PubMed2001

Comparing the similarity of time-series gene expression using signal processing metrics.

Many algorithms have been used to cluster genes measured by microarray across a time series. Instead of clustering, our goal was to compare all pairs of genes to determine whether there was evidence of a phase shift between them. We describe a technique where gene expression is treated as a discrete time-invariant signal, allowing the use of digital signal-processing tools, including power spectral density, coherence, and transfer gain and phase shift. We used these on a public RNA expression set of 2467 genes measured every 7 min for 119 min and found 18 putative associations. Two of these were known in the biomedical literature and may have been missed using correlation coefficients. Digital signal processing tools can be embedded and enhance existing clustering algorithms.

Algorithms↗
PubMed2001

The personal internetworked notary and guardian.

In this paper, we propose a secure, distributed and scaleable infrastructure for a lifelong personal medical record system. We leverage on existing and widely available technologies, like the Web and public-key cryptography, to define an architecture that allows patients to exercise full control over their medical data. This is done without compromising patients' privacy and the ability of other interested parties (e.g. physicians, health-care institutions, public-health researchers) to access the data when appropriately authorized. The system organizes the information as a tree of encrypted plain-text XML files, in order to ensure platform independence and durability, and uses a role-based authorization scheme to assign access privileges. In addition to the basic architecture, we describe tools to populate the patient's record with data from hospital databases and the first testbed applications we are deploying.

Computer Security↗
PubMed2001

Corticotropin releasing hormone increases apparent potency of adrenocorticotropic hormone stimulation of cortisol secretion.

HYPOTHESIS: Corticotropin releasing hormone (CRH) has a regulatory effect on cortisol secretion in addition to its classic effect of stimulating adrenocorticotropic hormone (ACTH) secretion. REVIEW: There is growing evidence of "long-loop" and paracrine adrenal stimulation by CRH. Data from a study of the ovine-corticotropin releasing hormone (oCRH) stimulation test in 13 sexually abused girls and 13 normal controls was used in Montecarlo simulations of the hypothalamic-pituitary-adrenal axis, to get estimates of adrenal sensitivity to ACTH and cortisol elimination kinetics before and after oCRH administration. In both controls and sexually abused girls, ACTH had an apparent greater effect on cortisol secretion after administration of oCRH compared to its effect during the baseline period. This lends support to the hypothesis and suggests that it should be tested experimentally.

Adrenocorticotropic Hormone↗
PubMed2001

Determining significant fold differences in gene expression analysis.

A typical use for RNA expression microarrays is comparing the measurement of gene expression of two groups. There has not been a study reproducing an entire experiment and modeling the distribution of reproducibility of fold differences. Our goal was to create a model of significance for fold differences, then maximize the number of ESTs above that threshold. Multiple strategies were tested to filter out those ESTs contributing to noise, thus decreasing the requirements of what was needed for significance. We found that even though RNA expression levels appears consistent in duplicate measurements, when entire experiments are duplicated, the calculated fold differences are not as consistent. Thus, it is critically important to repeat as many data points as possible, to ensure that genes and ESTs labeled as significant are truly so. We were successfully able to use duplicated expression measurements to model the duplicated fold differences, and to calculate the levels of fold difference needed to reach significance. This approach can be applied to many other experiments to ascertain significance without a priori assumptions.

Expressed Sequence Tags↗
PubMed2001

Unsupervised learning from complex data: the matrix incision tree algorithm.

Analysis of large-scale gene expression data requires novel methods for knowledge discovery and predictive model building as well as clustering. Organizing data into meaningful structures is one of the most fundamental modes of learning. DNA microarray data set can be viewed as a set of mutually associated genes in a high-dimensional space. This paper describes a novel method to organize a complex high-dimensional space into successive lower-dimensional spaces based on the geometric properties of the data structure in the absence of a priori knowledge. The matrix incision tree algorithm reveals the hierarchical structural organization of observed data by determining the successive hyperplanes that 'optimally' separate the data hyperspace. The algorithm was tested against published data sets yielding promising results.

Algorithms↗
PubMed2001

On reporting fold differences.

As we enter an age in which genomics and bioinformatics make possible the discovery of new knowledge about the biological characteristics of an organism, it is critical that we attempt to report newly discovered "significant" phenotypes only when they are actually of significance. With the relative youth of genome-scale gene expression technologies, how to make such distinctions has yet to be better defined. We present a "mask technology" by which to filter out those levels of gene expression that fall within the noise of the experimental techniques being employed. Conversely, our technique can lend validation to significant fold differences in expression level even when the fold value may appear quite small (e.g. 1.3). Given array-organized expression level results from a pair of identical experiments, our ID Mask Tool enables the automated creation of a two-dimensional "region of insignificance" that can then be used with subsequent data analyses. Fundamentally, this should enable researchers to report on findings that are more likely to be in nature truly meaningful. Moreover, this can prevent major investments of time, energy, and biological resources into the pursuit of candidate genes that represent false positives.

Computational Biology↗
PubMed2001

Optimal data entry by patients: effects of interface structure and design.

UNLABELLED: Direct electronic acquisition of data from patients possesses accuracy and diagnostic value. The mechanics of how best to capture historical information from patients using electronic interfaces are not well studied. We undertook an iterative usability experiment to answer 2 questions: 1) How can maximal electronic data input from a patient be achieved, and 2) Do varying structures for data entry promote differential documentation of specified data elements? METHODS: A series of four trials comprised the testing cycle. Unstructured text entry, directed text entry, and closed ended questions were tested in combination against outcomes of word count, time to task completion, and user preferences. Covariates of interest included participants' technologic experience and ergonomic experience with keyboards, as well as self-report of educational status, literacy, and primary language. RESULTS: Participants clearly preferred the order of initial closed-ended questions followed by unstructured text entry, and this ordering was not associated with decrements in word count or increase in time. When compared to unstructured text entry, directed text entry provided higher documentation of data for past medical history and questions which parents wished to discuss with the clinician. A closed-end question structure, when compared to directed text entry, provided higher capture of parents' questions for discussion. CONCLUSIONS: Optimal design of an electronic interview for the capture of medical histories will benefit from a mixed structure of directed text entry and closed-ended questions. For historical or clinically relevant items where maximal capture of data is desired, a structure with closed-ended questions would be preferred.

Humans↗
PubMed2001

A web-based tool to retrieve human genome polymorphisms from public databases.

Single Nucleotide Polymorphisms (SNPs) are the most important source of variation in our genome, and an invaluable tool in the hands of researchers who investigate genetic diseases. Databases of SNPs are growing at a very fast rate, and the ability to perform large-scale, high-resolution association studies is quickly becoming a reality. In this paper we describe SNPper, a web-based tool to search for SNPs in public databases. The system allows searching for all SNPs in a given set of genes (for candidate gene studies) or in a specified region of a chromosome. The information displayed for each gene or each SNP is fully annotated and linked to the leading bioinformatics web sites. The first release of SNPper is available on the web, and has received positive feedback from the genetic and bioinformatics community.

Databases, Genetic↗
PubMed2001

Building ICU artifact detection models with more data in less time.

As many as 86% of intensive care unit (ICU) alarms are false. Multiple signal integration of temporal monitor data by decision tree induction may improve artifact detection. We explore the effect of data granularity on model-building by comparing models made from 1-second versus 1-minute data. Models developed from 1-minute data remained effective when tested on 1-second data. Model development using 1-minute data means that more hours of ICU monitoring (including more artifacts) can be processed in less time. Compression of temporal data by arithmetic mean, therefore, can be an effective method for decreasing knowledge discovery processing time without compromising learning.

Artifacts↗
PubMed2000

Discovering functional relationships between RNA expression and chemotherapeutic susceptibility using relevance networks.

In an effort to find gene regulatory networks and clusters of genes that affect cancer susceptibility to anticancer agents, we joined a database with baseline expression levels of 7,245 genes measured by using microarrays in 60 cancer cell lines, to a database with the amounts of 5,084 anticancer agents needed to inhibit growth of those same cell lines. Comprehensive pair-wise correlations were calculated between gene expression and measures of agent susceptibility. Associations weaker than a threshold strength were removed, leaving networks of highly correlated genes and agents called relevance networks. Hypotheses for potential single-gene determinants of anticancer agent susceptibility were constructed. The effect of random chance in the large number of calculations performed was empirically determined by repeated random permutation testing; only associations stronger than those seen in multiply permuted data were used in clustering. We discuss the advantages of this methodology over alternative approaches, such as phylogenetic-type tree clustering and self-organizing maps.

Antineoplastic Agents↗
PubMed2000

Growth and determinants of access in patient e-mail and Internet use.

OBJECTIVES: To measure the rate of access to and use of the Internet and e-mail, to determine sociodemographic predictors of access, and to measure the change in Internet and e-mail access over a 1-year interval. DESIGN: Survey study. Comparison of data with those from a similar survey from 1998. SETTING: Emergency department of a large urban pediatric teaching hospital. PARTICIPANTS: Primary caretakers of pediatric patients or the patients themselves if aged 16 years or older. MAIN OUTCOME MEASURES: Use of and access to the Internet or e-mail. RESULTS: We surveyed 214 individuals: 72.8% use or have access to the Internet, e-mail, or both, an increase from 52.2% in the 1998 survey (P<.001), and 48.5% regularly use the Internet or e-mail, compared with 43.1% in 1998 (P = .32). Outside the home, access is primarily at work (52.2%), schools (8.9%), public libraries (11.5%), and friends' and relatives' houses (16.7%). Internet use and access are linearly correlated with income (r = 0.43; P<.001). White patients are more likely to have access (odds ratio, 2.6; 95% confidence interval, 1.3-5.4; P<.001) than black or Asian patients, whereas those of Hispanic ethnicity are less likely to have access (odds ratio, 0.20; 95% confidence interval, 0.09-0.43; P<.001). However, after adjustment for race and Hispanic ethnicity, only income was a significant predictor of family access to the Internet and e-mail. CONCLUSIONS: During the past year, many patients have gained access to the Internet and e-mail, although rates of regular use have remained steady. This access is often from outside the home. Furthermore, access is directly related to income and is unevenly distributed across racial and ethnic groups.

Adolescent↗
PubMed2000

Parents as direct contributors to the medical record: validation of their electronic input.

STUDY OBJECTIVES: We assessed the validity and completeness of data in the past medical history (PMH) obtained electronically from parents and examined effects of the human-computer interface and sociodemographic variables on electronic parental report. METHODS: We compared parents' electronic report of PMH data with a criterion standard, structured face-to-face interview by a pediatrician blinded to the electronic data. The electronic medical record interface enabled parents to provide 5 elements of the PMH: birth status, allergies, current medications, immunization status, and previous hospitalizations. The setting was the emergency department waiting room in an academic, urban children's hospital; parents of infants up to 12 months old participated. Outcome measures were validity of the PMH data obtained using the electronic medical record interface and odds of having an invalid or incomplete response using the electronic medical record interface. RESULTS: One hundred parents were enrolled (69.4% of eligible subjects). Study subjects did not differ from nonenrollees on demographic variables and visit characteristics. The validity of the electronic medical record interface data was high across the PMH elements (94% to 99%). Two demographic features predicted invalid response: parental primary language other than English or Spanish (odds ratio [OR] 11.4, 95% confidence interval CI 1.7 to 76.3), and Asian ethnicity (OR 14. 6, 95% CI 1.2 to 182.4). Incomplete responses were predicted by limited previous experience with computers; computer-naive subjects had an eightfold increased odds of skipping a question (OR 7.9, 95% CI 1.8 to 34.6). CONCLUSION: Parents are accurate independent reporters of their infants' general PMH using the electronic medical record interface. Their participation in care may be enhanced by allowing them to contribute medical information directly to the electronic medical record.

Attitude to Computers↗