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PubMed2001

Intratumor genetic heterogeneity in advanced human colorectal adenocarcinoma.

Colorectal carcinogenesis is widely accepted as one of the best-characterized examples of stepwise progression. The existing colorectal carcinogenesis model assumes genetic homogeneity of individual tumors for the main known genetic alterations: K-ras and p53 genes point mutations and loss of heterozygosity (LOH) of chromosome 5q and 18q. The object of the present study was to demonstrate the existence of an intratumor genetic heterogeneity in advanced sporadic colorectal carcinoma for these genetic alterations. Using improved tissue microdissection and DNA extraction, for each tumor, amplifiable DNA was obtained from 15 to 20 areas, of which 1 to 2 concerned lymph node metastases (LNM). This study revealed that 10 of 15 (67%) analyzed tumors were heterogeneous for at least 1 genetic alteration, with between 2 and 6 genotypically different clones detected per tumor. No correlation was observed between the genotype of these subclones and histological differentiation or invasive propensity. Intratumor heterogeneity was more frequently observed for LOH than for point mutations, 67% and 58% for LOH at APC and DCC locus, and 20% for mutation of either the K-ras or p53 gene. In 5 of the 9 (56%) heterogeneous cases with available LNM, the genotype observed in the LNM was different from that of the main clone in the primary tumor, and moreover, 2 of the LNM displayed a genotype undetected in the primary tumor. In conclusion, intratumor genetic heterogeneity was demonstrated in advanced sporadic colorectal carcinoma and was represented as topographically distinct genotypic subclones. Taking into account such a significant genetic heterogeneity of colorectal tumors, the use of genetic markers for prognosis management should be reconsidered.

Adenocarcinoma↗
PubMed1999

Dynamically heterogenous partitions and phylogenetic inference: an evaluation of analytical strategies with cytochrome b and ND6 gene sequences in cranes.

ki ctes over whether molecular sequence data should be partitioned for phylogenetic analysis often confound two types of heterogeneity among partitions. We distinguish historical heterogeneity (i.e., different partitions have different evolutionary relationships) from dynamic heterogeneity (i.e., different partitions show different patterns of sequence evolution) and explore the impact of the latter on phylogenetic accuracy and precision with a two-gene, mitochondrial data set for cranes. The well-established phylogeny of cranes allows us to contrast tree-based estimates of relevant parameter values with estimates based on pairwise comparisons and to ascertain the effects of incorporating different amounts of process information into phylogenetic estimates. We show that codon positions in the cytochrome b and NADH dehydrogenase subunit 6 genes are dynamically heterogenous under both Poisson and invariable-sites + gamma-rates versions of the F84 model and that heterogeneity includes variation in base composition and transition bias as well as substitution rate. Estimates of transition-bias and relative-rate parameters from pairwise sequence comparisons were comparable to those obtained as tree-based maximum likelihood estimates. Neither rate-category nor mixed-model partitioning strategies resulted in a loss of phylogenetic precision relative to unpartitioned analyses. We suggest that weighted-average distances provide a computationally feasible alternative to direct maximum likelihood estimates of phylogeny for mixed-model analyses of large, dynamically heterogenous data sets.

Algorithms↗
PubMed2006

A heterogeneity-based genome search meta-analysis for autism-spectrum disorders.

Autism and autism-spectrum disorders exhibit high heritability, although specific susceptibility genes still remain largely elusive. We performed a heterogeneity-based genome search meta-analysis (HEGESMA) of nine genome scans on autism or autism-spectrum disorders. Each genome scan was separated in 30 cM bins and the maximum linkage statistic from each bin was ranked. Significance for each bin's average rank and for between-scan heterogeneity (dis-similarity in the average ranks) was obtained through Monte Carlo tests. For autism, data from 771 affected sibpairs were synthesized across six separate genome scans. Region 7q22-q32 reached genome-wide significance both in weighted and unweighted analyses, with evidence for significantly low between-scan heterogeneity. The flanking chromosomal region 7q32-qter reached the less stringent threshold of suggestive significance, with no evidence for low between-scan heterogeneity. For autism-spectrum disorders (634 affected sibpairs from five separate scans), no chromosomal region reached genome-wide significance. However, suggestive significance was reached for the chromosomal regions 17p11.2-q12 and 10p12-q11.1 in weighted analyses. There was evidence for significantly high between-scan heterogeneity for the former region. The meta-analysis suggests that the 7q22-q32 region should be further scrutinized for autism susceptibility genes, while autism-spectrum disorders seem to have quite diverse linkage signals across scans, possibly suggesting genetic heterogeneity across subsyndromes and subpopulations.

Asperger Syndrome↗
PubMed2001

Genetic heterogeneity and clonal evolution in neuroblastoma.

Tumour heterogeneity and clonal evolution at the genetic level may explain the development of malignant or resistant disease during clinical progression of neuroblastoma (NB). In this report we use 1p allelic analysis and DNA ploidy to evaluate clonal heterogeneity and clonal selection in vivo. We studied a total of 69 tumours from 29 patients with NB. To evaluate tumour heterogeneity and clonal evolution in vivo we used a panel of polymorphic allelic markers mapping to chromosome 1. 33 tumours from 12 patients (group 1) were obtained from different sites during the same surgery or at sequential surgeries without intervening chemotherapy to evaluate genetic heterogeneity. Paired samples from 10 patients (group 2) were used to evaluate clonal selection before and after chemotherapy. In 6 cases paired tumours and derived cell lines were studied. Analysis of DNA ploidy changes by karyotype, FISH and flow cytometry was performed in 15 tumours from 6 multiply recurred local-regional (LR) NB patients. Allelotype study revealed that 66% (8/12) of group 1 samples were heterogeneous, with distinct allelic patterns in tumour samples separated by time or location. In group 2 allelic patterns were different in post-chemotherapy specimens in 60% (6/10). DNA ploidy analysis showed that pre-chemotherapy samples contained 2 distinct ploidy clones, one diploid and one triploid, whereas all post-chemotherapy tumor samples were 100% diploid. These findings suggest that NB exhibits a high degree of clonal heterogeneity and clonal evolution occurs during the course of therapy and clinical progression.

Chromosomes, Human, Pair 1↗
PubMed2005

The significance of tumor heterogeneity for prediction of DNA ploidy of prostate cancer.

OBJECTIVE: In a previous study, we mapped the ploidy heterogeneity of prostate cancer using flow cytometry in 676 tumor samples from 50 radical prostatectomy specimens. Ploidy heterogeneity was common (42% of tumors) and was found in all non-diploid tumors. The volume of non-diploid tumor was estimated and found to predict extra-prostatic extension and seminal vesicle invasion. The aim of this study was to evaluate the impact of tumor heterogeneity on preoperative ploidy assessment. MATERIAL AND METHODS: In 50 men at least six core biopsies were taken before prostatectomy. Sections from biopsies with cancer were Feulgen-stained for image cytometry. After exclusion of biopsies with insufficient material, 123 histograms from 48 men (mean 2.6; range 1-7) remained for analysis. RESULTS: In 32 men, biopsies were diploid. In 16 men, at least one biopsy was non-diploid (14 tetraploid, two aneuploid) and 10 of them also had diploid biopsies. In 34 men (71%), the prostatectomy specimens were correctly predicted as being either diploid (48%) or non-diploid (23%). The sensitivity and specificity of biopsies for predicting non-diploid cancer were 55% and 82%, respectively, and the positive and negative predictive values were 69% and 72%, respectively. The ploidy status of tumors with and without ploidy heterogeneity was correctly predicted in 55% and 82% of cases, respectively (p=0.04). Biopsies underestimated ploidy in 9/20 tumors (45%) with heterogeneous ploidy status. Underestimation mainly occurred when one or two cores were analyzed. CONCLUSIONS: Preoperative prediction of the ploidy status of prostate cancer is hampered by tumor heterogeneity. Analysis of multiple biopsies is important for correct preoperative ploidy estimation.

Aged↗
PubMed1996

Controversy of oral contraceptives and risk of rheumatoid arthritis: meta-analysis of conflicting studies and review of conflicting meta-analyses with special emphasis on analysis of heterogeneity.

The authors analyze the heterogeneity present in the combined results of past observational studies that investigated the association between oral contraceptive use and rheumatoid arthritis. The authors also evaluate discrepancies among meta-analyses that focus on the same relation. Of the 15 initially reviewed studies, 10 were selected for this meta-analysis, which also includes a qualitative summary of study characteristics and a critical appraisal of study quality. The authors used the direct method to combine the study results when there was no evidence of heterogeneity and the DerSimonian-Laird method when heterogeneity was present. Using a meta-regression to assess the sources of heterogeneity, the authors weighted summary estimates by sample size and undertook a sensitivity analysis. There was a strong indication of heterogeneity when combining all studies (x2 = 29.34, p = 0.00060) with the source of controls explaining most of the heterogeneity. The most important factor in explaining the differences among the overall summary estimates given by the meta-analyses is that different effect estimates had been selected for the same studies. There is no conclusive evidence of a protective effect of oral contraceptives on the risk of developing rheumatoid arthritis. Consensus is needed on how meta-analyses of observational studies should be conducted.

Arthritis, Rheumatoid↗
PubMed1997

Heterogeneity of DNA distribution pattern in renal tumours.

The presence of intratumoural heterogeneity in DNA distribution patterns has been accepted. However, most previous studies have not taken this fact into consideration. The value of DNA cytometry depends on its reproducibility. This could be influenced by heterogeneity failure. The aim of the present study is to evaluate intratumoural heterogeneity in renal cell cancer. A sample of 22 tumours of the kidney was investigated by means of static DNA cytometry: 21 tumours were carcinomas, one was an angiomyolipoma. Probes from seven different locations of each tumour were Feulgen-stained and measured. The variability of DNA features was determined and correlated with histological grade and type and with tumour size. There was considerable intratumoural heterogeneity with respect to DNA distribution pattern in 45% of the tumours. Additional non-diploid tumour-stemlines and deviation of computed DNA features could be found in several cases by measuring more than one slide per tumour. A correlation between tumour heterogeneity, grading or typing, and tumour size could not be found. Because these DNA parameters could serve as the foundation of a risk-adapted treatment, tumour heterogeneity could have clinical consequences. Based on the results of this study we suggest measuring at least three slides per tumour to avoid misinterpretation of DNA measurements in renal cell cancer.

Adult↗
PubMed1996

Does matrix-assisted laser desorption/ionization mass spectrometry allow analysis of carbohydrate heterogeneity in glycoproteins? A study of natural human interferon-gamma.

Interferon-gamma (IFN-gamma) is a dimeric, secretory glycoprotein produced by T-lymphocytes. The glycan micro-heterogeneity of natural human IFN-gamma was characterized by matrix-assisted laser desorption/ionization mass spectrometry (MALDI/MS) combined with glycosidase digestion. The glycan structures at the two potential glycosylation sites, asparagine 25 and 97, differ in composition and heterogeneity. The glycan at Asn 25 consists of a mixture of hybrid structures and fucosylated complex bi-, tri- and tetra-antennary structures, whereas the glycan at Asn 97 is more heterogeneous and consists of a mixture of high mannose structures, hybrid structures and unfucosylated complex bi- and tri-antennary structures. The contribution to the observed glycan heterogeneity by prompt and metastable fragmentation was evaluated by treatments with different exoglycosidases and by comparison of linear, reflected and delayed extraction MALDI/TOF mass spectra. Heterogeneity observed with the matrices alpha-cyano-4-hydroxycinnamic acid, 2,5-dihydroxybenzoic acid and 2,4,6-trihydroxyacetophenone was compared. Most of the heterogeneity can be attributed to native structure diversity and only to a minor extent to mass spectrometric fragmentation such as fragmentational loss of sialic acid residues.

Carbohydrates↗
PubMed1993

Prognostic value of karyometric and clinical characteristics in renal cell carcinoma. Quantitative assessment of tumor heterogeneity.

BACKGROUND: The variation in tumor cell differentiation within one renal cell carcinoma, also termed tumor heterogeneity, renders visual tumor grading of these carcinomas difficult. Karyometric analysis enables description of nuclear characteristics of multiple tumor areas. Hence, karyometric analysis can be used to quantify tumor heterogeneity and thus may aid in a more objective grading of renal cell carcinoma. METHODS: In 121 patients with renal cell carcinoma (tumors in International Union Against Cancer [UICC] stages I [5 cases], II [23 cases], III [33 cases], and IV [60 cases]), clinical and karyometric features were studied to obtain routinely applicable prognostic factors. Several parts of the tumor were analyzed to obtain a measure of tumor heterogeneity. Univariate and multivariate Cox regression analyses were used to determine the predictive value of karyometric features independent of tumor stage and other clinical characteristics. RESULTS: The Cox univariate regression analysis showed correlation of several clinical and karyometric characteristics with survival. Of the clinical characteristics, TNM stage, tumor size, weight reduction, and performance status were significantly associated with survival. The karyometric features, especially those measurements associated with tumor heterogeneity (e.g. differences in nuclear size or chromatin texture between tumor subpopulations) were of value in predicting prognosis. In the Cox multivariate regression analysis, the Robson and UICC stages proved to be the most powerful predictors of survival (P < 0.0001). Of the clinical features, weight reduction and performance score were the only characteristics offering additional information regarding tumor stage (P < 0.0001). From the karyometric analysis quantification of anisokaryosis in the tumor at time of diagnosis offered additional prognostic information. Moreover, the differences of karyometric features within the tumor presumably associated with tumor heterogeneity correlated with survival. Using the features from the multivariate analysis, prognostic groups could be defined. CONCLUSION: We conclude that karyometric analysis offers a useful means for quantifying tumor heterogeneity. Multivariate Cox analysis revealed additional value of a grading system based on karyometric analysis to tumor stage. Karyometric analysis can be a useful tool for stratification of patient populations.

Adult↗
PubMed1993

DNA stem line heterogeneity in esophageal cancer accurately identified by flow cytometric analysis.

BACKGROUND: This study was designed to evaluate the importance of DNA stem line heterogeneity in determining the malignant potential of esophageal cancer. METHODS: Flow cytometric analysis of intratumor heterogeneity of DNA contents was performed on step-sectioned slices of 57 resected esophageal carcinomas. RESULTS: DNA stem line heterogeneity, as assessed by DNA content measurements, was present in 25 (44%) tumors; 6 (11%) were a combination of diploid and aneuploid DNA pattern, and 19 (33%) had two or more aneuploid peaks with different DNA contents (multiploid). Of the remaining 32 homogeneous tumors, 4 showed only a diploid DNA pattern in all samples examined, whereas 28 tumors had only the aneuploid pattern. Tumors with the heterogeneous DNA pattern had a significantly higher frequency of lymph node metastasis than did those with the homogeneous DNA pattern (P < 0.05). CONCLUSIONS: For evaluation of the highly malignant potential of esophageal carcinoma by nuclear DNA contents, it is important to identify accurately intratumoral heterogeneity. Because different DNA stem lines were evident in different areas of the lesion, evaluation of multiple specimens from a wide area of each lesion is needed to determine with accuracy the degree of intratumor DNA stem line heterogeneity.

Adult↗
PubMed2000

Heterogeneity and statistical significance in meta-analysis: an empirical study of 125 meta-analyses.

For meta-analysis, substantial uncertainty remains about the most appropriate statistical methods for combining the results of separate trials. An important issue for meta-analysis is how to incorporate heterogeneity, defined as variation among the results of individual trials beyond that expected from chance, into summary estimates of treatment effect. Another consideration is which 'metric' to use to measure treatment effect; for trials with binary outcomes, there are several possible metrics, including the odds ratio (a relative measure) and risk difference (an absolute measure). To examine empirically how assessment of treatment effect and heterogeneity may differ when different methods are utilized, we studied 125 meta-analyses representative of those performed by clinical investigators. There was no meta-analysis in which the summary risk difference and odds ratio were discrepant to the extent that one indicated significant benefit while the other indicated significant harm. Further, for most meta-analyses, summary odds ratios and risk differences agreed in statistical significance, leading to similar conclusions about whether treatments affected outcome. Heterogeneity was common regardless of whether treatment effects were measured by odds ratios or risk differences. However, risk differences usually displayed more heterogeneity than odds ratios. Random effects estimates, which incorporate heterogeneity, tended to be less precisely estimated than fixed effects estimates. We present two exceptions to these observations, which derive from the weights assigned to individual trial estimates. We discuss the implications of these findings for selection of a metric for meta-analysis and incorporation of heterogeneity into summary estimates. Published in 2000 by John Wiley & Sons, Ltd.

Bias↗
PubMed2003

Homogeneous and heterogeneous catalysis: bridging the gap through surface organometallic chemistry.

Surface organometallic chemistry is an area of heterogeneous catalysis which has recently emerged as a result of a comparative analysis of homogeneous and heterogeneous catalysis. The chemical industry has often favored heterogeneous catalysis, but the development of better catalysts has been hindered by the presence of numerous kinds of active sites and also by the low concentration of active sites. These factors have precluded a rational improvement of these systems, hence the empirical nature of heterogeneous catalysis. Catalysis is primarily a molecular phenomenon, and it must involve well-defined surface organometallic intermediates and/or transition states. Thus, one must be able to construct a well-defined active site, test its catalytic performance, and assess a structure-activity relationship, which will be used, in turn-as in homogeneous catalysis-to design better catalysts. By the transfer of the concepts and tools of molecular organometallic chemistry to surfaces, surface organometallic chemistry can generate well-defined surface species by understanding the reaction of organometallic complexes with the support, which can be considered as a rigid ligand. This new approach to heterogeneous catalysis can bring molecular insight to the design of new catalysts and even allow the discovery of new reactions (Ziegler-Natta depolymerization and alkane metathesis). After more than a century of existence, heterogeneous catalysis can still be improved and will play a crucial role in solving current problems. It offers an answer to economical and environmental problems faced by industry in the production of molecules (agrochemicals, petrochemicals, pharmaceuticals, polymers, basic chemicals).

Journal Article↗
PubMed1996

Use of excluded volume to increase the heterogeneity of pore size in agarose gels.

When testing theoretical models that quantitatively describe the sieving of macromolecules during gel electrophoresis, investigators have been limited by absence of control of the heterogeneity of the size of pores in the gel. In a recent study performed by electron microscopy of thin sections (G. A. Griess et al., J. Struct. Biol. 1993, III, 39-47), pore size heterogeneity has been increased for agarose gels by a combination of both derivatization and molecular weight reduction of the polysaccharide chains of agarose. In the present study, pore size heterogeneity is increased by a mechanism that appears to have an origin different from the origin of this previously observed increase in heterogeneity: Pore size heterogeneity is increased by addition of a polyethylene glycol (PEG) of high molecular weight (18,500) to molten agarose before gelation. In contrast, the use of a lower molecular weight PEG (either 4,000 or 7,500) causes the formation of micron-sized precipitates within a gelled network of agarose fibers. Thus far, the PEG-induced heterogeneity of pore size occurs primarily in 100-1,000 microns scale zones separated from each other by interzone regions of decreased agarose fiber density. More uniform gels are needed for the study of sieving.

Dose-Response Relationship, Drug↗
PubMedDate not supplied

Heterogeneity of the in vitro growth patterns in adult T-cell leukemia cells.

Adult T-cell leukemia (ATL) presents heterogeneous clinical features, especially in its clinical course. To clarify the differences in the cell characteristics of these heterogeneous forms, we studied in vitro growth of ATL cells. Nine ATL patients were divided into two groups; 5 acute (group A) and 4 chronic (group B). Although in vitro spontaneous growth was observed only in 3 out of 5 cases in group A, the growth patterns were heterogeneous. When crude interleukin 2 (IL-2) was added to the culture, cells from all the cases in Group A showed marked proliferative responses; these patterns were also heterogeneous. On the other hand, cells in group B displayed no or poor response. The degree of Tac (IL-2 receptor) expression was high in group A but low in group B. These observations suggest that clinical heterogeneity might reflect, at least in part, the cellular heterogeneity in IL-2 responsiveness as seen in vitro.

Adult↗
PubMed1988

Cell-to-cell heterogeneity in the expression of carbohydrate-based epitopes of a mucin-type glycoprotein on the surface of human mammary carcinoma cells.

A large, O-linked glycoprotein, termed PAS-O, is a major differentiation antigen on the surface of normal lactating breast epithelia and is also found on the surface of many mammary tumors and mammary carcinoma cell lines. A characteristic feature of populations of tumor cells that express PAS-O is the cell-to-cell heterogeneity with respect to the presence or absence of the molecule. In this study, we used the human mammary carcinoma line 734B and a set of six monoclonal antibodies reactive with PAS-O to study the basis of this heterogeneity. Extensive Western blot analysis of antibody binding to PAS-O in milk fat globule membranes and in skim milk revealed that the antibodies all recognized different epitopes of PAS-O. Moreover, the epitopes were destroyed by periodic acid oxidation, demonstrating their oligosaccharide basis. All six monoclonal antibodies stained the 734B cells heterogeneously. In addition, five clones derived from the parent 734B population also exhibited heterogeneity in the expression of each of the epitopes. An analysis of staining of the 734B clones revealed that, in some cases, certain cells within the cloned population stained with one monoclonal antibody but not with another antibody. Significantly, though, when the 734B cells were treated with neuraminidase prior to antibody staining, most of the heterogeneity was eliminated, and all but one of the monoclonal antibodies stained 90-100% of the cells. This increase in cell staining was matched by an increase in PAS-O staining on Western blots. We conclude that heterogeneity in PAS-O expression on 734B cells is due partly to masking of epitopes by sialic acid and a variation (on a cell-to-cell basis) in the extent of PAS-O sialylation.

Antibodies, Monoclonal↗
PubMed2005

Intratumor heterogeneity in blood perfusion in orthotopic human melanoma xenografts assessed by dynamic contrast-enhanced magnetic resonance imaging.

PURPOSE: To determine the intratumor heterogeneity in blood perfusion of orthotopic human melanoma xenografts by use of gadopentetate dimeglumine (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). MATERIALS AND METHODS: Orthotopic xenografts of an amelanotic human melanoma cell line (A-07) were scanned sagittally, coronally, and axially in three subsequent DCE-MRI sessions, using spoiled gradient recalled sequences, a voxel size of 0.31x0.62x2.0 mm3, and an interleaving acquisition method to avoid slice gaps. Tumor images of E . F (E is initial extraction fraction and F is perfusion) were produced by subjecting the DCE-MRI data to Kety analysis. E . F was used as a parameter for tumor blood perfusion, since E for Gd-DTPA is close to unity in A-07 tumors. RESULTS: All A-07 tumors subjected to investigation showed anisotropic radial heterogeneity in blood perfusion. The blood perfusion was low in the center of the tumors and increased toward the tumor periphery in the cranial, dorsal, caudal, and ventral directions, but not in the lateral and medial directions. In addition, 9 of 10 tumors showed blood perfusion hot spots in central or nonperipheral regions. The hot spots differed significantly between tumors in size, shape, location, and intensity, and appeared to be governed by stochastic processes. This heterogeneity superimposed the radial heterogeneity, but did not overshadow it in any tumor. CONCLUSION: Orthotopic human melanoma xenografts show significant intratumor heterogeneity in blood perfusion. This heterogeneity is made up of two distinctly different components, one stochastic and one nonstochastic radial component. The radial component is anisotropic and dominant and is superimposed by the stochastic component.

Animals↗
PubMed2004

Consequences of event rate heterogeneity across non-randomized study sub-groups.

Analyses to compare non-randomized groups are more and more common in both post hoc analyses of randomized clinical trials data and in analyses of long-term observational data. In such cases, it is quite likely that there are unknown or uncollected sources of heterogeneity in event rates. Research has shown that an underlying source of heterogeneity in event rates which is not included in proportional hazards regression models leads to biased estimates for included covariate effect estimates and lower power to test them whether the source of heterogeneity is assumed to be fixed or random. We demonstrate here using several post hoc analyses of clinical trials data that a potentially common problem may be that the non-randomized groups which are to be compared have differential variability in their event rates. We then show through simulation that such underlying heterogeneity which varies across the groups, when ignored in the modelling, can lead to an attenuated regression effect estimate for comparing the two groups to each other, lower rejection rates for the effect, and Wald-based confidence intervals with potentially much lower coverage than nominal. When the groups are not significantly different, but heterogeneity differs between them, an analysis ignoring the heterogeneity can even result in a significant negative comparison.

Clinical Trials as Topic↗
PubMed2001

Heterogeneous database integration in biomedicine.

The rapid expansion of biomedical knowledge, reduction in computing costs, and spread of internet access have created an ocean of electronic data. The decentralized nature of our scientific community and healthcare system, however, has resulted in a patchwork of diverse, or heterogeneous, database implementations, making access to and aggregation of data across databases very difficult. The database heterogeneity problem applies equally to clinical data describing individual patients and biological data characterizing our genome. Specifically, databases are highly heterogeneous with respect to the data models they employ, the data schemas they specify, the query languages they support, and the terminologies they recognize. Heterogeneous database systems attempt to unify disparate databases by providing uniform conceptual schemas that resolve representational heterogeneities, and by providing querying capabilities that aggregate and integrate distributed data. Research in this area has applied a variety of database and knowledge-based techniques, including semantic data modeling, ontology definition, query translation, query optimization, and terminology mapping. Existing systems have addressed heterogeneous database integration in the realms of molecular biology, hospital information systems, and application portability.

Computational Biology↗