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PubMed2004

Intratumor heterogeneity of cancer/testis antigens expression in human cutaneous melanoma is methylation-regulated and functionally reverted by 5-aza-2'-deoxycytidine.

Cancer/testis antigens (CTA) are suitable targets for immunotherapy of human malignancies, and clinical trials are mainly focusing on MAGE-A3. However, the heterogeneous intratumor expression of CTA may hamper the effectiveness of CTA-directed vaccination through the emergence of CTA-negative neoplastic clones. We investigated the intratumor heterogeneity of CTA in human melanoma and the underlying molecular mechanism(s) at clonal level using 14 single cell clones generated from the melanoma lesion Mel 313. Reverse transcription-PCR revealed a highly heterogeneous expression of MAGE-A1, -A2, -A3, -A4, -A6, GAGE 1-6, SSX 1-5, and PRAME among melanoma clones. Only nine clones expressed MAGE-A3 and competitive reverse transcription-PCR identified relative differences in the number of mRNA molecules of up to 130-fold between clones 5 and 14. This clonal heterogeneity of MAGE-A3 expression correlated with the methylation status of specific CpG dinucleotides in MAGE-A3 promoter: i.e., hypomethylated CpG dinucleotides at positions -321, -151, -19, -16, -5, -2, +21, and +42 were found in clones expressing high but not low levels of MAGE-A3. Supporting the role of DNA methylation in generating the intratumor heterogeneity of CTA, the DNA hypomethylating agent 5-aza-2'-deoxycytidine (5-AZA-dCyd) invariably induced their expression in all CTA-negative clones. Furthermore, 5-AZA-dCyd-treatment reduced to 6 folds the differential expression of MAGE-A3 between clones 5 and 14, which became recognized to a similar extent by T cells specific for a MAGE-A-encoded peptide. These findings identify promoter methylation as directly responsible for the intratumoral heterogeneity of therapeutic CTA in melanoma and foresee the use of 5-AZA-dCyd to overcome the limitations set by their intratumor heterogeneous expression to CTA-based vaccine therapy.

Antigens, Neoplasm↗
PubMed1995

Fractionated electrograms from a computer model of heterogeneously uncoupled anisotropic ventricular myocardium.

BACKGROUND: The relation between heterogeneously coupled myocardium and fractionated electrograms is incompletely understood. The purpose of this study was to use a detailed computer model of nonuniformly anisotropic myocardium to test the hypothesis that spatial variation of morphology of electrograms recorded simultaneously from multiple sites increases with increasing heterogeneity of intercellular coupling. METHODS AND RESULTS: A sheet of elements with Beeler-Reuter ionic kinetics was coupled with cytoplasmic resistivity to model cells. Gap junctional resistance values were assigned by recursive randomization to produce a fractal pattern of heterogeneous coupling, simulating damage resulting from infarction. The correlation dimension of the pattern, D, measured heterogeneity of intercellular coupling. The peak-to-peak amplitude, duration, minimum derivative (steepest downslope), number of inflections, frequency of peak power, and bandwidth of unfiltered unipolar electrograms were calculated. Linear regressions indicate (P < .001) that the coefficient of variation of five electrogram metrics increases with increasing substrate heterogeneity and that the distance over which electrogram morphology decorrelates decreases with increasing heterogeneity of intercellular coupling. CONCLUSIONS: These findings confirm our hypothesis that the spatial variation of morphology of electrograms recorded simultaneously from multiple sites increases with increasing heterogeneity of intercellular coupling.

Anisotropy↗
PubMed1999

Effects of IKr and IKs heterogeneity on action potential duration and its rate dependence: a simulation study.

BACKGROUND: A growing body of evidence suggests that heterogeneity of ion channel expression and electrophysiological characteristics is an important property of the ventricular myocardium. The 2 components of the delayed rectifier potassium current, IKr (rapid) and IKs (slow), play a dominant role in the repolarization of the action potential and are important determinants of its duration. METHODS AND RESULTS: In this report, the effects of heterogeneities of IKr and IKs on action potential duration (APD) and its rate dependence (adaptation) are studied with the use of the LRd model of a mammalian ventricular cell. Results demonstrate the importance of IKs density variations in heterogeneity of repolarization. Cells with reduced IKs (eg, mid-myocardial M cells) display long APD and steep dependence of APD on rate. Mechanistically, accumulation of IKs activation and increased sodium calcium exchange current, INaCa, secondary to Na+ accumulation at a fast rate underlie the steep APD-rate relation of these cells. When cells are electrotonically coupled in a multicellular fiber through resistive gap junction, APD differences are reduced. The results demonstrate strong dependence of APD heterogeneity on the degree of intercellular coupling even in the normal physiological range. Highly reduced coupling maximizes APD heterogeneity. CONCLUSIONS: Heterogeneity of IKs:IKr density strongly influences APD and its rate dependence. However, in the intact myocardium, the degree of gap-junction coupling may be an important factor that determines the manifestation of APD heterogeneity and dispersion of repolarization. The clinical significance of this study is in the context of repolarization abnormalities and associated arrhythmias (eg, long QT syndrome and torsade de pointes).

Action Potentials↗
PubMed1996

Fundamental cellular heterogeneity of the exocrine pancreas.

Homogeneity in structure and function are broadly assumed to be characteristics of the acinar pancreatic digestive enzyme-secreting tissue. In recent years, physiological studies have shown that the pancreas stores the digestive enzymes in heterogeneously composed pools and releases them from these pools in a cyclic and secretagoguec fashion. The cellular basis for pancreatic heterogeneity is unknown; classical light and electron microscopic preparations appear homogeneous. We applied a panel of biotinylated lectins to pancreatic tissue sections; acinar cell glycoconjugates were localized in situ with peroxidase and fluorescent techniques and lectin-gold complexes. The lectin-binding properties of both fasting rabbit and rat pancreas revealed extensive and specific heterogeneity of the acinar cell population. Light and electron microscopy demonstrated highly heterogeneous labeling of the zymogen granule contents of specific acinar cells with the lectins Ulex europaeus agglutinin (UEA) and Erythrina cristagalli (ECA), which also showed preferential labeling of peri-insular acini. Other lectins also demonstrated heterogeneous binding to specific cellular regions. The striking acinar cell heterogeneity confirms earlier predictions, and may eventually prove to be the cellular basis for the secretion of different enzyme mixtures from heterogeneous sources within the pancreas.

Animals↗
PubMed2004

Evaluating heterogeneity in cumulative meta-analyses.

BACKGROUND: Recently developed measures such as I2 and H allow the evaluation of the impact of heterogeneity in conventional meta-analyses. There has been no examination of the development of heterogeneity in the context of a cumulative meta-analysis. METHODS: Cumulative meta-analyses of five smoking cessation interventions (clonidine, nicotine replacement therapy using gum and patch, physician advice and acupuncture) were used to calculate I2 and H. These values were plotted by year of publication, control event rate and sample size to trace the development of heterogeneity over these covariates. RESULTS: The cumulative evaluation of heterogeneity varied according to the measure of heterogeneity used and the basis of cumulation. Plots produced from the calculations revealed areas of heterogeneity useful in the consideration of potential sources for further study. CONCLUSION: The examination of heterogeneity in conjunction with summary effect estimates in a cumulative meta-analysis offered valuable insight into the evolution of variation. Such information is not available in the context of conventional meta-analysis and has the potential to lead to the development of a richer picture of the effectiveness of interventions.

Acupuncture↗
PubMed1992

Power of likelihood ratio tests for heterogeneity of intraclass correlation and variance in balanced half-sib designs.

Statistical power of likelihood ratio tests was investigated for detection of heterogeneous variances and intraclass correlation in balanced half-sib designs. Powers of likelihood ratio tests were obtained from simulations. For half-sib designs of sires nested within herds, true intraclass correlations and phenotypic variances, and estimates thereof, were repeatedly sampled, and likelihood ratio tests were conducted. The power for detecting heterogeneity of intraclass correlations was low, but the power for detecting heterogeneous phenotypic variances was nearly always 100%. For balanced cross-classified designs, sires had progeny in all herds, and data were simulated by assuming that heterogeneity of between- and within-sire components was the result of a herd-dependent scale effect. Using this model, the power to detect heterogeneous between-sire components was substantially higher than the corresponding power to detect heterogeneous intraclass correlations in the nested design. It seems unlikely that reliable inference about heterogeneity of genetic variances or heritabilities between individual herds from daily cattle field data can be made.

Analysis of Variance↗
PubMed2004

A comparison of different heterogeneous proximity functions and Euclidean distance.

Proximity functions evaluate distances or similarities between objects. Unlike the Euclidean distance, heterogeneous proximity functions process variables differently according to their scale. The correct evaluation of nominal variables, whose values are unordered, is especially important. We compared five heterogeneous functions with the Euclidean distance to study whether functions sensitive to scale are better than a function assuming the same scale. In addition, we were interested of the relative performance of the five heterogeneous functions. The performance of the functions was measured with a nearest neighbor classifier that was applied to 12 medical data sets characterized with different scales. Unexpectedly, the performance of heterogeneous functions did not differ significantly from that of the Euclidean distance. As expected, significant differences between the Heterogeneous Value Difference Metric (HVDM) and the four value-matching-based heterogeneous functions favored HVDM. Additional research is needed to explain why heterogeneous functions did not outperform the Euclidean distance.

Artificial Intelligence↗
PubMed2006

Deconfounding microarray analysis - independent measurements of cell type proportions used in a regression model to resolve tissue heterogeneity bias.

OBJECTIVES: Microarray analysis requires standardized specimens and evaluation procedures to achieve acceptable results. A major limitation of this method is caused by heterogeneity in the cellular composition of tissue specimens, which frequently confounds data analysis. We introduce a linear model to deconfound gene expression data from tissue heterogeneity for genes exclusively expressed by a single cell type. METHODS: Gene expression data are deconfounded from tissue heterogeneity effects by analyzing them using an appropriate linear regression model. In our illustrating data set tissue heterogeneity is being measured using flow cytometry. Gene expression data are determined in parallel by real time quantitative polymerase chain reaction (qPCR) and microarray analyses. Verification of deconfounding is enabled using protein quantification for the respective marker genes. RESULTS: For our illustrating dataset, quantification of cell type proportions for peripheral blood mononuclear cells (PBMC) from tuberculosis patients and controls revealed differences in B cell and monocyte proportions between both study groups, and thus heterogeneity for the tissue under investigation. Gene expression analyses reflected these differences in celltype distribution. Fitting an appropriate linear model allowed us to deconfound measured transcriptome levels from tissue heterogeneity effects. In the case of monocytes, additional differential expression on the single cell level could be proposed. Protein quantification verified these deconfounded results. CONCLUSIONS: Deconfounding of transcriptome analyses for cellular heterogeneity greatly improves interpretability, and hence the validity of transcriptome profiling results.

Cell Physiological Phenomena↗
PubMed2006

Bayesian random-effect model for predicting outcome fraught with heterogeneity--an illustration with episodes of 44 patients with intractable epilepsy.

OBJECTIVE: The study aimed to develop a predictive model to deal with data fraught with heterogeneity that cannot be explained by sampling variation or measured covariates. METHODS: The random-effect Poisson regression model was first proposed to deal with over-dispersion for data fraught with heterogeneity after making allowance for measured covariates. Bayesian acyclic graphic model in conjunction with Markov Chain Monte Carlo (MCMC) technique was then applied to estimate the parameters of both relevant covariates and random effect. Predictive distribution was then generated to compare the predicted with the observed for the Bayesian model with and without random effect. Data from repeated measurement of episodes among 44 patients with intractable epilepsy were used as an illustration. RESULTS: The application of Poisson regression without taking heterogeneity into account to epilepsy data yielded a large value of heterogeneity (heterogeneity factor = 17.90, deviance = 1485, degree of freedom (df) = 83). After taking the random effect into account, the value of heterogeneity factor was greatly reduced (heterogeneity factor = 0.52, deviance = 42.5, df = 81). The Pearson chi2 for the comparison between the expected seizure frequencies and the observed ones at two and three months of the model with and without random effect were 34.27 (p = 1.00) and 1799.90 (p < 0.0001), respectively. CONCLUSION: The Bayesian acyclic model using the MCMC method was demonstrated to have great potential for disease prediction while data show over-dispersion attributed either to correlated property or to subject-to-subject variability.

Adolescent↗
PubMed1985

Immunochemical heterogeneity of human plasma high density lipoproteins. Identification with apolipoprotein A-I- and A-II-specific monoclonal antibodies.

Three mouse monoclonal antibodies specific for human apolipoprotein (apo) A-I and one specific for human apo-A-II were characterized with respect to their binding of high density lipoprotein (HDL) particles in solution. The apo-A-II-specific antibody bound 85% of 125I-HDL and 100% of soluble 125I-apo-A-II. However, none of the apo-A-I-specific antibodies bound greater than 60% of either HDL or soluble apo-A-I. Technical issues such as limiting amounts of antibody or antigen, radioiodination of the ligands, unavailability of the epitopes for reaction with antibody, selective binding of apo-A-I isoforms, and individual allotypic differences in apo-A-I were not responsible for the observed incomplete binding of all HDL and apo-A-I. The results suggested the existence of intrinsic immunochemical heterogeneity of apo-A-I both as organized on HDL as well as in free apo-A-I in solution. The validity of this observed heterogeneity was supported by demonstrating that (i) increased binding of HDL occurred when each of the apo-A-I antibodies was combined to form an oligoclonal antibody mixture, and (ii) 100% binding of HDL occurred when two apo-A-I antibodies were combined with the single apo-A-II antibody. To understand the basis for the heterogeneity of expression of apo-A-I epitopes on HDL, two hypotheses were examined. The first hypothesis that these apo-A-I antibodies distinguished apo-A-I molecules from different synthetic sources was not substantiated. Two of the antibodies bound epitopes on apo-A-I molecules in both thoracic duct lymph as an enriched source of intestinal HDL and the culture supernatants of the hepatic cell line Hep G2 as a source of hepatic HDL. The second hypothesis that the antibodies identified differences in the expression of apo-A-I on HDL subpopulations that were distinguished on the basis of size or net particle charge, i.e. organizational heterogeneity, appeared to provide the best available explanation for the immunochemical heterogeneity of apo-A-I in HDL. Relative differences in the expression of three distinct apo-A-I epitopes were demonstrated in HDL subpopulations obtained by either density gradient ultracentrifugation or chromatofocusing. In light of these studies, we conclude that there is intrinsic heterogeneity in the expression of intramolecular loci representing the apo-A-I epitopes identified by our monoclonal antibodies. Such heterogeneity must be considered in analysis of the biology and physiology of apo-A-I and lipoprotein particles bearing this chain.

Animals↗
PubMed1989

[Ultrastructural evaluation of pulmonary adenocarcinoma. II. Phenotype heterogeneity and classification].

A phenotypical heterogeneity was observed in 45 tumours (45 per cent) from a group of 102 carcinomas with ultrastructural features of exocrine differentiation. Double heterogeneity was found in 36 tumours and a triple one in 8 tumours; a case with quadruple heterogeneity was presented analogy of which has been lacking in literature. A combination of different exocrine phenotypes occurred in 12 tumours, exocrine and endocrine phenotypes combined in 18 tumours, exocrine cells and keratinocytes were found in 21 tumours. The exocrine phenotype was characterized usually (38 times) by secretion granules mostly of a serous type (19 times), cells with microvillous specialization without granules represented (15 times) a lower level of the exocrine phenotypical differentiation. A ciliary phenotype which could not produce homogenous population of dividing cells yet occurred (4 times) as a rudimentary accompaniment of an endocrine phenotype. The case of quadruple heterogeneity combined ciliary, serous, endocrine and keratinocytic phenotypes. The WHO histological typing scheme does not offer a proper category for heterogenous adenocarcinomas with one prevailing exocrine phenotype when compared with an analogous group of "combined" small cell carcinomas. Histological typing of such heterogenous adenocarcinomas is to be completed at least by an electron microscopical prevailing cytological characteristic in the same way as in phenotypically homogenous carcinomas. Heterogenous tumours without any phenotypical prevalence may form a group of mixed carcinomas which has been represented so far only by the histological types of adenosquamous and mucoepidermoid carcinoma.

Adenocarcinoma↗
PubMed1984

Macrophage heterogeneity.

Macrophages perform a large number of diverse and on occasion mutually antagonistic functions. It seems unlikely given the magnitude of the task, that any one cell could carry out all these different demands. This raises the possibility that distinct subsets of macrophages exist each capable of performing only certain functions. It is indeed the case that although all macrophages have many features in common they are by no means uniform. Two major types of macrophage heterogeneity have been described. The first is termed "Interpopulation" heterogeneity and refers to differences between populations of macrophages obtained from different tissue sites. The second is termed "Intrapopulation" heterogeneity and refers to differences between subpopulations of macrophages obtained from within a particular site. We propose that such macrophage heterogeneity could be generated by 2 main mechanisms--"Differentiation and Modulation". It is assumed that as macrophages differentiate from bone marrow precursor cells they sequentially express a series of functionally distinct phenotypes. Such phenotypes are however relatively dynamic and may be readily altered by exposure to various microenvironmental and nonmicroenvironmental modulating signals. The responsiveness of cells to modulating signals is likely to depend both on their differentiation stage and previous exposure to other such signals. Assuming that the cells entering different tissue sites are essentially identical, then "Interpopulation" heterogeneity may be generated as a direct result of different microenvironmental modulating signals acting on the cells. "Intrapopulation" heterogeneity on the other hand may be generated by both differentiation and modulation. Macrophages at various differentiation stages are found within a tissue. Some cells will have recently arrived from the blood stream while others may have resided in the tissue for some time. In addition, the cells within a tissue may have been exposed to a different spectrum of modulating signals, or exposed to the same signals for various periods of time. The suggested existence of distinct macrophage sublineages adds an additional level of complexity to the subject of macrophage heterogeneity. It has been shown in a relatively small number of experiments that colonies of macrophages, clonogenically derived from individual bone marrow precursor cells in vitro, may express different phenotypes.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1983

Significance of the molecular heterogeneity of gut hormones.

Molecular heterogeneity is a fundamental feature of ribosomally synthesized proteins and polypeptides. The heterogeneity reflects gene duplications with subsequent differences in mutation of the genes, different post-transcriptional and post-translational processings and different amino acid modifications. Gut hormones are also heterogeneous, but the degree of heterogeneity reported so far for each hormone has varied. The most extensively studied (i.e. cholecystokinins, gastrins, opioid peptides and glucagons) have displayed a high degree off heterogeneity. Similar degrees will probably emerge for the remaining gut hormones when they have been studied in greater detail. In accordance with the nature of the molecular difference, a distinction between macro- and microheterogeneity is proposed. Macroheterogeneity is caused by variations in peptide chain length; microheterogeneity by derivatizations or substitutions in single amino acid residues. The molecular heterogeneity has profound implications for measurement and study of a gut hormone. Thus, measurement in biological fluids requires careful evaluation of the number and affinity of different molecular forms. Understanding of the function and pathophysiology of gut hormones requires full clarification of their molecular heterogeneity.

Amino Acid Sequence↗
PubMed1995

Somatic heterogeneity of the CTG repeat in myotonic dystrophy is age and size dependent.

The most common form of adult muscular dystrophy, myotonic dystrophy (DM), is caused by the abnormal expansion of the CTG repeat, located in the 3' UTR of the DM gene. The expanded-CTG allele often presents as a diffused band on Southern blot analysis, suggesting somatic mosaicism. In order to study the somatic instability of the CTG repeat, we have investigated the dynamics of the size heterogeneity of the CTG expansion. Size heterogeneity is shown as a smear on Southern blot and is measured by the midpeak-width ratio of the expanded allele to the normal sized allele. The ratio is also corrected for compression in the higher-molecular-weight region. It is found that the size heterogeneity of the expanded-CTG repeats, of 173 DM patients, correlates well with the age of the patient (r = .81, P << .001). The older patients show larger size variation. This correlation is independent of the sex of either the patient or the transmitting parent. The size heterogeneity of the expansion, based on age groups, is also dependent on the size of the expanded trinucleotide repeat. However, obvious size heterogeneity is not observed in congenital cases, regardless of the size of expansion. Comparison of individual patient samples collected at two different times has confirmed that the degree of size heterogeneity increases with age and has revealed a subtle but definite upward shift in the size of the expanded-CTG allele. The progression of the CTG repeat toward larger expansion with age is further confirmed by small-pool PCR assay that resolved the heterogeneous fragments into discrete bands.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1997

Heterogeneity in dynamic regulation of intracellular calcium in airway smooth muscle cells.

Intracellular Ca2+ ([Ca2+]i) regulation in smooth muscle involves multiple mechanisms such as second messengers and ion channels. Intra- and inter-cellular heterogeneities in these mechanisms are likely, and will be reflected by heterogeneities in [Ca2+]i. In the present study, real-time confocal imaging was used to examine intracellular and intercellular heterogeneity in spontaneous Ca2+ sparks and acetylcholine-induced [Ca2+]i oscillations in porcine tracheal smooth muscle (TSM) cells. Ca2+ sparks were highly localized to multiple (2-5) foci in a cell. Individual sparks displayed relatively constant rise times (14.5 +/- 0.3% variance) and amplitudes (11.1 +/- 0.2% variance), but across regions these attributes varied. The incidence of sparks was often coupled across adjacent regions (r2 = 0.93 +/- 0.04). Spark frequency was increased approximately 350% by ryanodine and caffeine, suggesting that they represent unitary Ca2+ release through ryanodine receptor (RyR) channels. In TSM cells, acetylcholine induced [Ca2+]i oscillations that initiated from foci with the highest spark frequency. Results using beta-escin-permeabilized TSM cells indicated that [Ca2+]i oscillations also represent Ca2+ release through RyR channels. [Ca2+]i oscillations displayed intracellular heterogeneity in amplitude (30 +/- 4% variance) and intercellular heterogeneities in amplitude (100-800 nM) and frequency (5-35 per minute). Within a region, the amplitude and frequency of [Ca2+]i oscillations were correlated to both acetylcholine concentration (r = -0.79 +/- 0.04 for amplitude and 0.77 +/- 0.05 for frequency) and basal [Ca2+]i level (r = -0.94 +/- 0.02 for amplitude and 0.84 +/- 0.03 for frequency). Compared with TSM cells, acetylcholine-induced [Ca2+]i oscillations in bronchial cells were slower and lower in amplitude. We conclude that intracellular and intercellular heterogeneity in [Ca2+]i levels in airway smooth muscle reflects heterogeneities in Ca2+ regulatory mechanisms.

Acetylcholine↗
PubMed1996

Heterogeneity of B-lymphoid tumors in E mu-myc transgenic mice.

The clinically important issue of tumor heterogeneity was studied in C57BL/6-E mu-myc transgenic mice, which provide a genetically uniform model system in which all animals eventually develop B cell lymphomas after additional genetic changes beyond enforced expression of the transgenic oncogene. Three different approaches were compared for discerning the cellular and genetic homogeneity of these tumors. Analysis of Igh gene rearrangement showed mainly monoclonality and only infrequent oligoclonality in the tumors from a given animal. In contrast, cytogenetic examination indicated a substantial degree of heterogeneity in the tumors from a given animal and showed that a wide variety of secondary genetic changes occur in E mu-myc transgenic mice. Flow cytometry of DNA content also revealed a high degree of heterogeneity within and among the tumor masses from single E mu-myc mice. Estimates of tumor heterogeneity revealed by these three techniques often did not coincide, indicating that these different approaches reflect distinct cellular parameters. Transgenic E mu-myc mice additionally homozygous for the scid mutation displayed enhanced levels of secondary genetic changes that were valuable for the methodological comparisons performed here, and demonstrated that the extent of tumor heterogeneity can be influenced by specific genes other than the primary E mu-myc transgene. In summary, a combination of methodologies appears to be required to reveal the full extent of tumor heterogeneity within a single individual.

Animals↗
PubMed2004

Heterogeneity of risk for melanoma and pancreatic and digestive malignancies: a melanoma case-control study.

BACKGROUND: Data addressing the interfamilial heterogeneity of melanoma are limited. In the current study, the authors assessed melanoma risk according to family history of melanoma and other melanoma-associated malignancies and evaluated the familial heterogeneity of melanomas, pancreatic malignancies, and gastrointestinal malignancies. METHODS: The authors obtained patient histories of malignancy in first-degree relatives as part of a clinic-based case-control study. The case group included 737 newly diagnosed patients with invasive melanoma, and the control group included 1021 outpatients from clinics at the same medical centers. To assess heterogeneity of risk among families affected by melanoma, a nonparametric method was used to detect extrabinomial variation. In addition, selected patients with melanoma (n=133) were tested for germline mutations in CDKN2A. RESULTS: The adjusted odds ratio associated with a family history of melanoma was 1.7 (95% confidence interval, 1.1-2.7). Family histories of pancreatic, gastrointestinal, brain, breast, or lymphoproliferative disease did not increase the risk of melanoma significantly. Among case families, significant evidence of familial heterogeneity was found for melanomas, but not for pancreatic or gastrointestinal malignancies. Two mutations in CDKN2A previously associated with melanoma risk were identified among the 133 patients tested in the case group; mutation detection did not differ between families with low and high heterogeneity scores. CONCLUSIONS: Familial heterogeneity testing in the study population did not improve the selection of high-risk families for genetic study. Even in a large case-control study, few families that had multiple members with melanoma were identified, and family members with pancreatic malignancies were rare.

Adult↗
PubMed2004

Evaluations of maximization procedures for estimating linkage parameters under heterogeneity.

Locus heterogeneity is a major problem plaguing the mapping of disease genes responsible for complex genetic traits via linkage analysis. A common feature of several available methods to account for heterogeneity is that they involve maximizing a multidimensional likelihood to obtain maximum likelihood estimates. The high dimensionality of the likelihood surface may be due to multiple heterogeneity (mixing) parameters, linkage parameters, and/or regression coefficients corresponding to multiple covariates. Here, we focus on this nontrivial computational aspect of incorporating heterogeneity by considering several likelihood maximization procedures, including the expectation maximization (EM) algorithm and the stochastic expectation maximization (SEM) algorithm. The wide applicability of these procedures is demonstrated first through a general formulation of accounting for heterogeneity, and then by applying them to two specific formulations. Furthermore, our simulation studies as well as an application to the Genetic Analysis Workshop 12 asthma datasets show that, among other observations, SEM performs better than EM. As an aside, we illustrate a limitation of the popular admixture approach for incorporating heterogeneity, proved elsewhere. We also show how to obtain standard errors (SEs) for EM and SEM estimates, using methods available in the literature. These SEs can then be combined with the corresponding estimates to provide confidence intervals of the parameters.

Algorithms↗