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Search Results: 1 - 10 of 1688 matches for " Isaac Kohane "
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No small matter: qualitatively distinct challenges of pediatric genomic studies
Isaac S Kohane
Genome Medicine , 2011, DOI: 10.1186/gm278
Abstract: There is more here than just the usual underfunding of pediatric projects relative to adult projects, although this certainly may be an important factor [1]. In many ways the barriers mirror some of those that cause under-representation of historically under-represented and underserved minorities in genetic studies as outlined by Francis Collins and colleagues [2]. One important consideration is that it is just much harder to perform genetic studies with children. To start with, there is the matter of consent and assent. Children are not children forever and therefore the parental consent most likely has to be eventually replaced by childhood assent and then full consent as they reach maturity [3]. This already imposes significantly more in terms of overheads for consent management than those incurred by adult prospective studies.Then there is the challenge of obtaining the biological sample. In the judgment of many parents, most children, and a few institutional review boards, the pain and small risks of venipuncture for blood samples outweigh potential benefits, particularly for healthy children. The alternative (for example, obtaining saliva as a source of DNA) often results in suboptimal genomic analyses due to difficulties in obtaining an adequate quantity of sample in young children.In addition, most pediatric care is delivered in small practices, and much of this care and ancillary measurements are not documented in the electronic health records that are mostly found in larger healthcare systems. This makes identification of cases and controls largely an expensive and manual operation. Moreover, the transition to adulthood almost always entails a change in healthcare provider and healthcare delivery system and therefore a discontinuity in record keeping (electronic and/or paper). This results in loss of follow-up information that is essential for genomic studies that address long-term outcomes.Perhaps most challenging is that there is not one population of ch
The twin questions of personalized medicine: who are you and whom do you most resemble?
Isaac S Kohane
Genome Medicine , 2009, DOI: 10.1186/gm4
Abstract: Wikipedia [1] defines personalized medicine as the "use of information and data from a patient's genotype, or level of gene expression to stratify disease, select a medication, provide a therapy, or initiate a preventative measure that is particularly suited to that patient at the time of administration." Other data types are then mentioned as being equally important. A more conventionally authoritative source [2] defines personalized medicine as "The use of genetic susceptibility or pharmacogenetic testing to tailor an individual's preventive care or drug therapy." This apparent primacy of molecular or genetic measurements obscures the fact that they are both only one of many clinical characterizations, and often not the most important one.An alternative definition, arising from more than 50 years of clinical decision science [3], holds that personalized medicine is the practice of clinical decision-making such that the decisions made maximize the outcomes that the patient most cares about and minimizes those that the patient fears the most, on the basis of as much knowledge about the individual's state as is available. To be able to contemplate such a personalized medicine practice, two fundamental questions have to be answered. First, what are the relevant patient characteristics? Second, which clinically distinct subgroup of patients does this patient most resemble?The second question defines the knowledge that we have about how a group of clinically relevant patients are likely to respond to a given intervention or what the accuracy and specificity of a particular test are when applied to that subgroup. The first question is important because the deeper our understanding of who the patient is, the more accurately we can identify which subgroup or subgroups (s)he might belong to, and the more accurately we can assess the level of confidence that the match to that group is relevant. Stated differently, information about the patient is of very limited utility with
GenePING: secure, scalable management of personal genomic data
Ben Adida, Isaac S Kohane
BMC Genomics , 2006, DOI: 10.1186/1471-2164-7-93
Abstract: We present the design and implementation of GenePING, an extension to the PING personal health record system that supports secure storage of large, genome-sized datasets, as well as efficient sharing and retrieval of individual datapoints (e.g. SNPs, rare mutations, gene expression levels). Even with full access to the raw GenePING storage, an attacker cannot discover any stored genomic datapoint on any single patient. Given a large-enough number of patient records, an attacker cannot discover which data corresponds to which patient, or even the size of a given patient's record. The computational overhead of GenePING's security features is a small constant, making the system usable, even in emergency care, on today's hardware.GenePING is the first personal health record management system to support the efficient and secure storage and sharing of large genomic datasets. GenePING is available online at http://ping.chip.org/genepinghtml webcite, licensed under the LGPL.Genomic data are becoming a routine component of clinical diagnosis and treatment. Prospective parents with familial or ethnic history of genetic disease have long been encouraged to undergo genetic counseling, including genotyping for disease alleles such as Tay-Sachs and Cystic Fibrosis [1,2]. Recent research [3], demonstrating that several treatment responses are conditional on genomic profile, promises to usher in the long-awaited era of personalized medicine, all based on the patient's gene sequence or gene expression signature.Clinically pertinent genomic data extends far beyond the patient's somatic genome sequence. Advanced cancer treatment options include genetic testing of cancer cells for specific markers, e.g. estrogen receptors in breast cancer or the Philadelphia chromosome in CML [4]. This type of diagnostic will likely expand into full genomic profiling of cancer cells to help determine appropriate treatment [5]. In addition, much recent literature has uncovered correlations between gene
A SNP-centric database for the investigation of the human genome
Alberto Riva, Isaac S Kohane
BMC Bioinformatics , 2004, DOI: 10.1186/1471-2105-5-33
Abstract: SNPper is a web-based application designed to facilitate the retrieval and use of human SNPs for high-throughput research purposes. It provides a rich local database generated by combining SNP data with the Human Genome sequence and with several other data sources, and offers the user a variety of querying, visualization and data export tools. In this paper we describe the structure and organization of the SNPper database, we review the available data export and visualization options, and we describe how the architecture of SNPper and its specialized data structures support high-volume SNP analysis.The rich annotation database and the powerful data manipulation and presentation facilities it offers make SNPper a very useful online resource for SNP research. Its success proves the great need for integrated and interoperable resources in the field of computational biology, and shows how such systems may play a critical role in supporting the large-scale computational analysis of our genome.Single Nucleotide Polymorphisms (SNPs) are an increasingly important tool for the study of the structure and history of our genome [1]. The most common application of SNPs is in association studies, that look for a statistically significant association between SNP alleles and phenotypes (usually diseases), in order to pinpoint candidate causative genes [2]. The power of association studies is a function of the number of SNPs used, and of their quality (defined here as the likelihood of the SNP locus actually being polymorphic in the population under study). For this reason, large databases of well-annotated SNPs have been developed, and are growing at an ever increasing rate.In order to take advantage of the mass of known SNPs, now numbering almost five millions for the human genome alone, researchers need tools to easily and efficiently locate the desired SNPs, to evaluate their annotations, and to export them in formats suitable for subsequent analysis. This, in turn, requires lar
Lower expression of genes near microRNA in C. elegans germline
Hidenori Inaoka, Yutaka Fukuoka, Isaac S Kohane
BMC Bioinformatics , 2006, DOI: 10.1186/1471-2105-7-112
Abstract: We analyzed gene expression levels around the 84 of 113 know miRNAs for which there are nearby gene that were measured in the data in two independent C. elegans expression data sets. The expression levels are lower for genes in the vicinity of 59 of 84 (71%) miRNAs as compared to genes far from such miRNAs. Analysis of the genes with lower expression in proximity to the miRNAs reveals increased frequency matching of the 7 nucleotide "seed"s of these miRNAs.We found decreased messenger RNA (mRNA) abundance, localized within a 10 kb of chromosomal distance of some miRNAs, in C. elegans germline. The increased frequency of seed matching near miRNA can explain, in part, the localized effects.MicroRNAs (miRNAs) are short (~22 nt-long) non-protein-coding RNAs. In metazoans, miRNA initially thought to be primarily involved in post-transcriptional control [1] have now been shown to have profound and tissue-specific effects on mRNA transcript abundance across significant fractions of the transcriptome [2]. Concurrently it has been demonstrated that miRNAs have a central role in development and organogenesis [3,4]. In the context of the apparent interactions between miRNA and transcriptional control and mounting evidence for the localized component of transcriptional control [5,6], we performed a genome-wide study of C. elegans to determine a) if there were localized effects of miRNA on transcription and b) if previously identified "seed matching" between miRNA and their gene targets could explain, in part, the observed decrease in expression around some miRNAs.First, the 113 known miRNAs in C. elegans were mapped to the worm genome and genes near each miRNAs were sought. Ninety-six miRNAs were found with at least one gene within 10 kb and 31 miRNA were found within the introns of protein-coding genes. Detailed information about the miRNAs is found in supplemental data. Two experiments of genome-wide expression profiling in C. elegans were analyzed. The first dataset by Kim e
A set of genes previously implicated in the hypoxia response might be an important modulator in the rat ear tissue response to mechanical stretch
Vishal Saxena, Dennis Orgill, Isaac Kohane
BMC Genomics , 2007, DOI: 10.1186/1471-2164-8-430
Abstract: With the use of AE, the hypoxia gene set was the most important at a highly significant level. A co-expression network analysis showed that important co-regulated members of the hypoxia pathway include a glucose transporter (slc2a8), heme oxygenase, and nitric oxide synthase2 among others.It appears that the hypoxia pathway may be an important modulator of response of soft tissue to forces. This finding gives us insights not only into the underlying biology, but also into clinical interventions that could be designed to mimic within wounded tissue the effects of forces without all the negative effects that forces themselves create.Worldwide, wounds pose a major health issue. Lower extremity ulcers alone cost the US Medicare system $1.5 billion. Unless wound therapies see a large improvement, we will see escalating treatment costs and morbidity as the population ages and as the incidence of diabetes and obesity increases. An understanding of the mechanisms underlying wound healing will shed light on how normal physiology adapts to changes in the normal homeostatic environment. The vacuum assisted closure (VAC) device (KCI, San Antonio Texas) is a relatively new modality in wound healing. Although the device has been shown to accelerate wound healing, its mode of action remains to be proven convincingly. Figure 1 shows the application of the device. This involves packing a polyurethane sponge into the wound bed and then sealing the wound including the sponge with an occlusive dressing that has one outlet tube going to a vacuum (a vacuum of about 115 mmHg is applied through the tube). Theories about how this device obtains its efficacy range from a reduction in bacterial load [1] to a reduction in edema. The blowup in Figure 1 shows that with the application of the vacuum the skin is pulled into the intra-strut spacings of the sponge thereby stretching the skin.In an earlier publication, we have used a numerical model to show how the imposition of the vacuum forces the
Inter-species differences of co-expression of neighboring genes in eukaryotic genomes
Yutaka Fukuoka, Hidenori Inaoka, Isaac S Kohane
BMC Genomics , 2004, DOI: 10.1186/1471-2164-5-4
Abstract: We analyzed 24 sets of expression data from the six species. Highly co-expressed pairs were sorted into bins of equal sized intervals of CD, and a co-expression rate (CoER) in each bin was calculated. In all datasets, a higher CoER was obtained in a short CD range than a long distance range. These results show that across all studied species, there was a consistent effect of CD on co-expression. However, the results using the ND show more diversity. Intra- and inter-species comparisons of CoER reveal that there are significant differences in the co-expression rates of neighboring genes among the species. A pair-wise BLAST analysis finds 8 – 30 % of the highly co-expressed pairs are duplic ated genes.We confirmed that in the six eukaryotic species, there was a consistent tendency that neighboring genes are likely to be co-expressed. Results of pair-wised BLAST indicate a significant effect of non-duplicated pairs on co-expression. A comparison of CD and ND suggests the dominant effect of CD.As a consequence of DNA sequencing activities, whole-genome sequences for many microbial organisms as well as eukaryotic species are available in publicly accessible databases. DNA microarray technology makes it possible to simultaneously monitor expression patterns of thousand of genes. Expression profiles combined with whole-genome information, especially map information, enable us to investigate a relationship between co-expression of genes and a chromosomal distance (CD).In the pioneering work in this field, Cohen et al. (2000) and Kruglyak and Tang (2000) independently showed that in yeast (Saccharomyces cerevisiae), adjacent pairs of genes show correlated expression [1,2]. In the nematode worm (Caenorhabditis elegans), a study of the relationship between physical distance and expression similarity found many co-expressed pairs of neighboring genes within a distance range of 20 kbp [3]. Clustering of co-expressed genes has been found in humans (Homo sapiens) [4], worm [5] and
Genes involved in complex adaptive processes tend to have highly conserved upstream regions in mammalian genomes
Soohyun Lee, Isaac Kohane, Simon Kasif
BMC Genomics , 2005, DOI: 10.1186/1471-2164-6-168
Abstract: By conducting a rank correlation analysis between functional annotation and upstream sequence alignment scores obtained by human-mouse and human-dog comparison, we found a significantly greater conservation of the upstream sequence of genes involved in development, cell communication, neural functions and signaling processes than those involved in more basic processes shared with unicellular organisms such as metabolism and ribosomal function. This observation persists after controlling for G+C content. Considering conservation as a functional signature, we hypothesize a higher density of cis-regulatory elements upstream of genes participating in complex and adaptive processes.We identified a class of functions that are associated with either high or low promoter conservation in mammals. We detected a significant tendency that points to complex and adaptive processes were associated with higher promoter conservation, despite the fact that they have emerged relatively recently during evolution. We described and contrasted several hypotheses that provide a deeper insight into how transcriptional complexity might have been emerged during evolution.Transcription regulation is among the most sophisticated of regulatory processes, involving a complex combinatorial selection of cis- and trans-acting signals [1]. Proximal upstream regions of a gene in particular contain many cis-regulatory elements that regulate the expression of the gene by binding to various transcription factors. Many of the cis-regulatory motifs have been successfully identified by phylogenetic footprinting, which makes use of cross-species sequence conservation as a functional signature [2-6]. Based on this rationalization, we aimed to test if the complexity of transcriptional regulation depends on gene function, by looking at the sequence conservation at the proximal upstream region. This is the first whole genome study providing statistical evidence of significant conservation in upstream regions of
Extracting Physician Group Intelligence from Electronic Health Records to Support Evidence Based Medicine
Griffin M. Weber, Isaac S. Kohane
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0064933
Abstract: Evidence-based medicine employs expert opinion and clinical data to inform clinical decision making. The objective of this study is to determine whether it is possible to complement these sources of evidence with information about physician “group intelligence” that exists in electronic health records. Specifically, we measured laboratory test “repeat intervals”, defined as the amount of time it takes for a physician to repeat a test that was previously ordered for the same patient. Our assumption is that while the result of a test is a direct measure of one marker of a patient's health, the physician's decision to order the test is based on multiple factors including past experience, available treatment options, and information about the patient that might not be coded in the electronic health record. By examining repeat intervals in aggregate over large numbers of patients, we show that it is possible to 1) determine what laboratory test results physicians consider “normal”, 2) identify subpopulations of patients that deviate from the norm, and 3) identify situations where laboratory tests are over-ordered. We used laboratory tests as just one example of how physician group intelligence can be used to support evidence based medicine in a way that is automated and continually updated.
Correction: What Are the Benefits and Risks of Fitting Patients with Radiofrequency Identification Devices?
Mark Levine,Ben Adida,Kenneth Mandl,Isaac Kohane,John Halamka
PLOS Medicine , 2008, DOI: 10.1371/journal.pmed.0050036
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