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PubMed2003

Clinical implications of incorporating heterogeneity corrections in mantle field irradiation.

PURPOSE: Patient dose calculations for mantle-field irradiation have traditionally been performed using homogeneous, water phantom data. The advent of computed tomography (CT)-based treatment planning now permits dose calculations to be corrected for actual patient density. Incorporation of full heterogeneity corrections is desirable, because calculations performed in this fashion more closely represent the actual dose delivered to the patient. In preparation for full clinical implementation of heterogeneity corrections in mantle irradiation, an evaluation of possible changes in dosimetry when transitioning from treatment plans generated without heterogeneity corrections to treatment plans that incorporated full heterogeneity corrections is presented. MATERIALS AND METHODS: A retrospective analysis was performed of treatment plans with and without heterogeneity corrections for 15 consecutive patients who had undergone full mantle-field irradiation. Comparisons were made of the absolute delivered doses (in cGy per monitor unit) and the absolute volume (in cubic centimeters) enclosed by the isodose surface of the 30.6 Gy prescription line and the surface representing 90% of the prescribed dose. Dose-volume histograms (DVHs) were generated and studied to evaluate differences in the doses received by the lungs, heart, and spinal cord between corrected and uncorrected plans. Comparisons were made of the volumes of lung receiving at least 20 Gy, the volumes of heart receiving at least 25.2 Gy, and the maximum cord dose. RESULTS: Dosimetric differences between heterogeneity-corrected and heterogeneity-uncorrected calculations were small. The mean total ratio of corrected-to-uncorrected dose per monitor unit was 1.01, with a standard deviation (SD) of 0.02. The mean corrected-to-uncorrected treated volume ratio (30.6 Gy) was 0.97, SD 0.14, and the mean corrected-to-uncorrected volume ratio of the 90% isodose surface was 0.99, SD 0.02. The ratio of the volume of lung receiving at least 20 Gy was 1.03, SD 0.02; the ratio of the volume of heart receiving at least 25.2 Gy was 1.01, SD 0.03; and the maximum spinal cord dose ratio was 1.02, SD 0.02. CONCLUSIONS: In all patient treatment plans evaluated, no significant dosimetric differences were observed between heterogeneity-corrected and heterogeneity-uncorrected treatment plans. However, unpredictable differences in the prescription isodose (30.6 Gy) were observed. The differences in coverage at the 90% isodose volume were negligible. The dose administered to lung in heterogeneity-corrected plans demonstrates a higher dose overall, with the greatest increase occurring at volumes receiving at least 20 Gy. In light of these small dosimetric differences, we believe that heterogeneity corrections can be incorporated into full mantle-field treatment planning.

Dose Fractionation, Radiation↗

PubMed1998

A realistic closed-form radiobiological model of clinical tumor-control data incorporating intertumor heterogeneity.

PURPOSE: To investigate the role of intertumor heterogeneity in clinical tumor control datasets and the relationship to in vitro measurements of tumor biopsy samples. Specifically, to develop a modified linear-quadratic (LQ) model incorporating such heterogeneity that it is practical to fit to clinical tumor-control datasets. METHODS AND MATERIALS: We developed a modified version of the linear-quadratic (LQ) model for tumor control, incorporating a (lagged) time factor to allow for tumor cell repopulation. We explicitly took into account the interpatient heterogeneity in clonogen number, radiosensitivity, and repopulation rate. Using this model, we could generate realistic TCP curves using parameter estimates consistent with those reported from in vitro studies, subject to the inclusion of a radiosensitivity (or dose)-modifying factor. We then demonstrated that the model was dominated by the heterogeneity in alpha (tumor radiosensitivity) and derived an approximate simplified model incorporating this heterogeneity. This simplified model is expressible in a compact closed form, which it is practical to fit to clinical datasets. Using two previously analysed datasets, we fit the model using direct maximum-likelihood techniques and obtained parameter estimates that were, again, consistent with the experimental data on the radiosensitivity of primary human tumor cells. This heterogeneity model includes the same number of adjustable parameters as the standard LQ model. RESULTS: The modified model provides parameter estimates that can easily be reconciled with the in vitro measurements. The simplified (approximate) form of the heterogeneity model is a compact, closed-form probit function that can readily be fitted to clinical series by conventional maximum-likelihood methodology. This heterogeneity model provides a slightly better fit to the datasets than the conventional LQ model, with the same numbers of fitted parameters. The parameter estimates of the clinically important time factors and lag periods are very similar to those obtained from the conventional LQ model, but with slightly narrower confidence intervals, reflecting the better fit to the clinical data. DISCUSSION: We have demonstrated, as have others, the importance of intertumor heterogeneity in the response of patient populations to radiotherapy. With the possible inclusion of a radiosensitivity-modifying factor (in vitro/in vivo) of around 1.7, the in vivo data can be made consistent with the in vitro SF2 and Tpot data. Fitting two previously analyzed multicenter datasets indicated that previous analyses based on conventional LQ models gave results for clinically important time factors and lags periods that were not significantly biased by the failure to include intertumor heterogeneity, with slightly narrower confidence intervals, reflecting the better fit to the clinical data. The simple closed-form model we have developed allows direct estimation of the heterogeneity in radiosensitivity within clinical series, and should prove useful in the analysis of other clinical series.

Dose-Response Relationship, Radiation↗

PubMed1996

A fractal approach to heterogeneous drug distribution: calcium pharmacokinetics.

PURPOSE: To point out the importance of heterogeneity in drug distribution processes and develop a noncompartmental approach for the description of the distribution of drug in the body. METHODS: A dichotomous branching network of vessels for the arterial tree connected to a similar venous network was used to describe the heterogeneity of blood flow in the successive generations of the networks. The relevant kinetics of drug distribution in the well perfused and the deep tissues was considered to take place under well stirred (homogeneous) and understirred (heterogeneous) conditions, respectively. RESULTS: A "homogeneous model" with classical kinetics (which is mathematically equivalent with the one-compartment model) was developed for these drugs which are confined to well perfused ("well stirred") spaces. A "heterogeneous model" was proposed for the drugs reaching understirred spaces using a decreasing with time rate coefficient (fractal kinetics) to model the diffusion of drug under heterogeneous conditions. The analysis of the model equations revealed that the homogeneous model can be considered as a special case of the heterogeneous model. Concentration-time plots of multiexponential type were generated using the heterogeneous model equation. The empirically used power functions of time for the analysis of calcium clearance curves, were found to be similar to the equation adhering to the heterogeneous model. Fittings comparable to multiexponential models were obtained when the heterogeneous model equation with only one adjustable parameter was applied to six sets of long period calcium data. CONCLUSIONS: The heterogeneous processes of drug distribution in the body can obey the principles of fractal kinetics. Calcium clearance curves were analysed with the heterogeneous model. The validity of multicompartmental models which are based on the concept of homogeneity to describe drug distribution should be reconsidered.

Calcium↗

PubMedDate not supplied

One-dimensional scatter-subtraction method for brachytherapy dose calculation near bounded heterogeneities.

Neglect of tissue and applicator heterogeneities in brachytherapy treatment planning is due in part to lack of accurate, general, and fast three-dimensional (3D) dose-computation algorithms. A novel dose-calculation algorithm that accounts for the lateral dimensions and location of the heterogeneity as well as its thickness has been developed. For simple 2D, water-equivalent density heterogeneities, the algorithm is shown to be applicable to a wide range of photon energies and is 500-1000 times more efficient than Monte Carlo photon-transport calculations. The model is based upon reducing the bounded 2D heterogeneity problem to two 1D problems by dividing the scattering volume into two regions: A cone-shaped region that subtends the heterogeneity with its apex at the source and the complementary cone that contributes scatter dose by diffusion around the heterogeneity. The input data consist of precalculated scatter-to-primary ratios (SPRs) for collimated isotropic point sources. The central-axis "mini-beam" problem for a slab heterogeneity is solved by a simple 1D scatter integration model that accounts for both the thickness of the heterogeneity and its location relative to the point of interest. The scatter contribution arising outside the mini-beam is modeled as the difference in SPRs corrected for transmission through the heterogeneity. The algorithm agrees, on average, with sample Monte Carlo calculations within 1% to 7% for 125I, 192Ir, and 100 keV point sources along the axes of water-equivalent cylindrical heterogeneities (rho = 0-12.6 g/cm3, 3.6, and 24 mm diameters, and dose-perturbation factors of 0.44-1.33 relative to the homogeneous case). The potential of generalizing the scatter-subtraction approach to encompass 3D heterogeneities, those consisting of high-atomic number media, and those of irregular shape, is discussed.

Algorithms↗

PubMed2003

Analysis of heterogeneity of atypia within melanocytic nevi.

BACKGROUND: Incisional biopsy of clinically atypical nevi continues to be a common practice. Questions can arise as to the adequacy of these partial biopsies. OBJECTIVE: To determine whether incisional (partial) biopsy specimens may be considered representative of the entire lesion, atypical nevi submitted to our dermatopathology laboratory were examined for the presence or absence of heterogeneity of atypia within the individual nevi. DESIGN: The study included 250 histologically atypical nevi that were selected consecutively from pigmented lesions that were submitted to our dermatopathology laboratory by community and academic dermatologists for histopathologic analysis. Also, 23 moderately to severely atypical and 25 severely atypical nevi from consecutive submissions were added for statistical reasons. Lesions with both clear and involved margins were used. Lesions were considered homogeneous if the atypia involved the entire lesion or heterogeneous if either the atypia was focal or if different degrees of atypia occurred within the same lesion. Atypia was defined by the usual parameters of architectural and cytologic atypia and host response. Also, the degree of atypia in relationship to heterogeneity and to patient age was determined. SETTING: The Dermatopathology Laboratory, University of California, Irvine. MAIN OUTCOME MEASURES: Outcome measures included the percentage of nevi exhibiting heterogeneity of atypia, heterogeneity of atypia in relation to patient age, degree of atypia in relation to patient age, and degree of atypia in relation to the presence of heterogeneity of atypia. RESULTS: Of the 298 nevi examined, 107 (35.9%) were heterogeneous in atypia and 191 (64.1%) were homogeneous in atypia. There was no significant difference in age between patients with heterogeneous lesions and those with homogeneous lesions. There was a statistically significant correlation between the degree of atypia and patient age. The average age of patients with a lesser degree of atypia was 36.9 years, while the average age of patients with a greater degree of atypia was 44.8 years (P<.005). There was no significant correlation between degree of atypia and heterogeneity of atypia (correlation coefficient, 0.1). CONCLUSIONS: A clinically significant proportion of atypical nevi exhibited heterogeneity of atypia. Also, there was a significant relationship between the degree of atypia and increasing age (P<.005). Therefore, if a clinically atypical nevus warrants a biopsy, these results give additional support for complete excisional biopsy (which can include shave or punch) to assure adequate histopathologic sampling of the lesion.

Adult↗

PubMed1997

Intratumoral heterogeneity in primary breast carcinoma: study of concurrent parameters.

BACKGROUND AND OBJECTIVE: Intratumoral heterogeneity for prognostic factors (ploidy, proliferation, hormone receptor positivity) has been demonstrated in primary breast carcinoma by both flow cytometric and image analysis methods. Previously, heterogeneity in tumors had been demonstrated for only singular parameters. Our objective, using maps of tumors in which discrete regions can be analyzed simultaneously for DNA index (DI) and proliferative activity, was to demonstrate heterogeneity with respect to two parameters and to determine whether any interparametric relationships existed. METHODS: We analyzed 25 cases of archived, paraffin-embedded breast carcinoma (ductal) for Feulgen stain DNA analysis and MIB-1 immunohistochemistry using the CAS 200 Image Cytometer. For each tumor, four discrete regions were analyzed including tumor-host tissue interface sectors. RESULTS: Of 25 cases, 19 (76%) were homogeneously diploid or near-diploid aneuploid, and 6 (24%) were heterogeneous. Within the heterogeneous group, all cases had at least one diploid and one or more aneuploid populations from separate discrete regions. Five of six DI heterogeneous tumors displayed diploid values for the overall measurements of the respective tumors, based on analysis of 200 or more nuclei. Eight of 25 cases (32%) showed significant measurable variation for MIB-1 proliferative activity in various sectors of tumor. All the MIB-1 heterogeneous tumors, with one exception, were homogeneously diploid. CONCLUSIONS: These findings demonstrate that (1) heterogeneity is present with respect to DI and proliferative activity in breast carcinoma and is relatively common, (2) tumors homogeneous for one parameter may be heterogeneous for another, and (3) heterogeneity for proliferative activity is more common in homogeneously diploid tumors than in heterogeneous/aneuploid tumors.

Breast Neoplasms↗

PubMed1998

Understanding and testing for heterogeneity across 2 x 2 tables: application to meta-analysis.

A question of interest in a meta-analysis is whether the studies considered are homogeneous. This paper addresses two forms of heterogeneity. Additive heterogeneity occurs when a particular treatment performs differently in different studies. Interactive heterogeneity occurs when the relative performance of two treatments varies with the study. This paper discusses the use and calculation of Bayes factors to test for both forms of heterogeneity. I consider three hierarchical models. One exhibits both forms of heterogeneity, a second exhibits only additive heterogeneity, and the third model has neither form of heterogeneity. I use a method based on bridge sampling for calculating the Bayes factors between the models. I consider two examples: in one both forms of heterogeneity seem to be present and in the other there seems to be additive heterogeneity but not interactive heterogeneity.

Antineoplastic Agents, Hormonal↗

PubMed2001

Intra- and intertumor heterogeneity in blood perfusion of human cervical cancer before treatment and after radiotherapy.

Knowledge of the intratumor heterogeneity in blood perfusion may lead to increased understanding of tumor response to treatment. In the present work, absolute perfusion values, in units of ml/g.min, were determined in 20 tumor subregions of patients with cervical cancer before treatment (n = 12) and after 2 weeks of radiotherapy (n = 8), by using a method based on contrast-enhanced magnetic resonance imaging. The aims were to evaluate the intratumor heterogeneity in perfusion in relation to the intertumor heterogeneity and to search for changes in the heterogeneities during the early phase of therapy. The intra- and intertumor heterogeneity in perfusion were estimated from components of one-way analyses of variance. The mean perfusion differed significantly among the patients before treatment, ranging from 0.044 to 0.12 ml/g x min. Large differences in perfusion were also observed within individual tumors. The heterogeneity was largest in the best perfused tumors, perfusion values ranging, e.g., from 0.055 to 0.29 ml/g x min were observed. The intratumor heterogeneity was similar to the intertumor heterogeneity. The mean perfusion generally increased or tended to increase during radiotherapy, ranging from 0.064 ml/g x min to 0.13 ml/g x min after 2 weeks of treatment. There was a tendency of increased intratumor heterogeneity in perfusion after therapy, consistent with the higher mean value; a difference in perfusion of more than a factor of 10 was seen within some tumors. These results suggest that cervix tumors contain a significant amount of poorly perfused subregions with high treatment resistance. Moreover, the perfusion and perfusion heterogeneity may increase during the early phase of radiotherapy and influence tumor response.

Carcinoma, Squamous Cell↗

PubMed2006

A simulation study comparing properties of heterogeneity measures in meta-analyses.

The assessment of heterogeneity or between-study variance is an important issue in meta-analysis. It determines the statistical methods to be used and the interpretation of the results. Tests of heterogeneity may be misleading either due to low power for sparse data or to the detection of irrelevant amounts of heterogeneity when many studies are involved. In the former case, notable heterogeneity may remain unconsidered and an unsuitable model may be chosen and the latter case may lead to unnecessary complex analyses strategies. Measures of heterogeneity are better suited to determine appropriate analyses strategies. We review two measures with different scaling and compare them with the heterogeneity test. Estimates of the within-study variance are discussed and a new total information measure is introduced. Various properties of the quantities in question are assessed by a simulation study. Heterogeneity test and measures are not directly related to the amount of between-study variance but to the relative increase of variance due to heterogeneity. It is more favourable to base the within-study variance estimate on the squared weights of individual studies than on the sum of weights. A heterogeneity measure scaled to a fixed interval needs reference values for proper interpretation. A measure defined by the relation of between- to within-study variance has a more natural interpretation but no upper limit. Both measures are quantifications of the impact of heterogeneity on the meta-analysis result as both depend on the variance of the individual study effects and thus on the number of patients in the studies.

Biomedical Research↗

PubMed2001

Effective parameters for two-phase flow in a porous medium with periodic heterogeneities.

Computational simulations of two-phase flow in porous media are used to investigate the feasibility of replacing a porous medium containing heterogeneities with an equivalent homogeneous medium. Simulations are performed for the case of infiltration of a dense nonaqueous phase liquid (DNAPL) in a water-saturated, heterogeneous porous medium. For two specific porous media, with periodic and rather simple heterogeneity patterns, the existence of a representative elementary volume (REV) is studied. Upscaled intrinsic permeabilities and upscaled nonlinear constitutive relationships for two-phase flow systems are numerically calculated and the effects of heterogeneities are evaluated. Upscaled capillary pressure-saturation curves for drainage are found to be distinctly different from the lower-scale curves for individual regions of heterogeneity. Irreducible water saturation for the homogenized medium is found to be much larger than the corresponding lower-scale values. Numerical simulations for both heterogeneous and homogeneous representations of the considered porous media are carried out. Although the homogenized model simulates the spreading behavior of DNAPL reasonably well, it still fails to match completely the results form the heterogeneous simulations. This seems to be due, in part, to the nonlinearities inherent to multiphase flow systems. Although we have focussed on a periodic heterogeneous medium in this study, our methodology is applicable to other forms of heterogeneous media. In particular, the procedure for identification of a REV, and associated upscaled constitutive relations, can be used for randomly heterogeneous or layered media as well.

Models, Theoretical↗

PubMed2003

Treatment planning for lung cancer: traditional homogeneous point-dose prescription compared with heterogeneity-corrected dose-volume prescription.

PURPOSE: To quantify the differences in doses to target volumes and critical thoracic structures calculated by traditional homogeneous point-dose prescription and heterogeneity-corrected volume-dose prescription. METHODS AND MATERIALS: Between 1998 and 2001, 30 patients with inoperable Stage I/II non-small-cell lung cancer underwent radiation treatment planning at our institution. A commercially available convolution/superposition- based algorithm was used. Three treatment plans were calculated for each patient using identical beam geometries: one plan was generated by traditional homogeneous point-dose prescription, a second by the traditional method with heterogeneity correction, and a third by heterogeneity-corrected volume-dose prescription that would cover 95% of the planned target volume (PTV). Target volume coverage, isocenter dose, and dose uniformity in the second and third plans were compared. RESULTS: The PTV, clinical target volume (CTV), and isocenter calculated by the heterogeneity-corrected volume-dose method were equivalent to those calculated by the traditional homogeneous point-dose method with heterogeneity correction. The fraction of the PTV covered by heterogeneity-corrected volume-dose prescription was significantly greater than the fraction covered by traditional homogeneous point-dose prescription with heterogeneity correction (p = 0.05). The dose prescribed using the traditional method would have been delivered to less than 90% of the PTV in 14 of 30 patients. There was no significant difference in the maximum and minimum doses to the PTV, the CTV, or the isocenter calculated by the traditional homogeneous method with heterogeneity correction and the heterogeneity-corrected volume-dose method. There was also no significant difference in the planned volume of lung receiving greater than 20 Gy as calculated by these two methods. CONCLUSION: When compared with traditional homogeneous radiation treatment planning, heterogeneity-corrected methods produce equivalent PTV, CTV, and isocenter doses while providing superior PTV coverage.

Carcinoma, Non-Small-Cell Lung↗

PubMed1976

Ontogeny of B-lymphocyte function. II. Ability of endotoxin to increase the heterogeneity of affinity of the immune response of B lymphocytes from fetal mice.

The ontogeny of the functional capacity of B lymphocytes to generate a heterogeneous response to a haptenic determinant was studied by cell transfer techniques in LAF1 mice. Fetal liver, as a source of B lymphocytes, was transferred into adult, syngeneic, irradiated animals. All recipients received excess adult thymus cells so that T-cell activity did not limit the response and were immunized with DNP-BGG. The heterogeneity of avidity of their anti-DNP PFC response was assayed by hapten inhibition of plaque formation. Animals reconstituted with B lymphocytes from fetal donors produced a response that is highly restricted with respect to heterogeneity of affinity. Transfer studies using multiple fetal donors or mixtures of adult and neonatal cells for reconstitution suggest that the restriction in heterogeneity is not the consequence of suppressor T-lymphocyte activity. With animals reconstituted with B cells from day 16 or older fetal donors, injection of LPS together with antigen converted the response to a heterogeneous "adult-type" response. With animals reconstituted with B lymphocytes from day 14 fetal liver DxSO4, but not LPS, could convert the response to a highly heterogeneous one. Animals reconstituted with day 14 or 16 fetal liver as source of B lymphocytes were capable of producing a heterogeneous secondary response despite the fact that their primary response was of restricted heterogeneity. This implies the selection of high affinity B-memory cells, in the absence of high affinity PFC during the primary response with fetal B lymphocytes. Animals reconstituted with day 14 or 16 fetal liver produce only direct PFC, while animals reconstituted with day 18 fetal liver produce both direct and indirect PFC. Three differentiation events have therefore been defined in the functional development of B lymphocytes: (a) between day 14 and day 16 of fetal life they acquire responsiveness to LPS; (B) BETWEEN DAY 16 AND 18 OF FETAL DEVELOPMENT THEY ACQUire the capacity to produce indirect PFC; (C) between day 7 and 10 after birth they acquire the capacity to give a heterogeneous response after normal immunization. In addition, it was shown that LAF1 mice already have all of the information required to produce an "adult-type" heterogeneous anti-DNP response at day 14 of fetal life.

Age Factors↗

PubMed1987

Heterogeneity of expression of apical membrane determinants in A6 epithelial cells.

Expression of apical membrane antigens by A6 cells is heterogeneous. The A6 cell line is a model system for sodium transport and hormone action in "tight" epithelia. To create probes for the study of sodium transport and aldosterone action, we generated monoclonal antibodies (MoAbs) by immunization of BALB/c mice with intact A6 cells. MoAbs binding to apical membrane determinants were selected by an enzyme-linked immunoadsorbance assay (ELISA) against the apical surface of confluent A6 monolayers. Examination of ELISA-positive MoAbs by indirect immunofluorescence on confluent cells grown on glass cover slips revealed heterogeneity of apical expression: individual cells comprising the monolayer were fluorescently labeled to variable degrees and some cells were unlabeled. Expression of one antigen, recognized by MoAb I4C1, was heterogeneous in cells at low density as well as for confluent cells. Another antibody, 2B8, exhibited heterogeneity of labeling in confluent A6 monolayers, but no labeling of any cells at low density. This heterogeneity of antigen expression suggested that A6 cells are not a single cell type. However, cloned A6 cells established by limiting dilution were also labeled heterogeneously by both antibodies. Thus the heterogeneity observed is not due to genetic inhomogeneity between cells. Expression of the antigens on apical membranes of cells grown on Millipore filters was heterogeneous for the antigen recognized by 2B8, but essentially homogeneous for that recognized by I4C1, suggesting that the degree of differentiation of the cells plays a role in the heterogeneous expression of apical antigens. This heterogeneity of expression of apical antigens adds new complexity to the study of A6 cells and the differentiation of epithelial cells in culture.

Animals↗

PubMed2002

Carotid plaque ultrasonic heterogeneity and severity of stenosis.

BACKGROUND AND PURPOSE: Several studies have reported on the correlation of ultrasonic carotid plaque morphology, cerebrovascular symptoms, and intraplaque hemorrhage. This study correlates ultrasonic carotid plaque morphology with the degree of carotid stenosis. METHODS: Carotid arteries (n=2460) were examined by using color duplex ultrasound during a 1-year period. Carotid stenoses were classified into <50%, 50% to <60%, 60% to <70%, and >70% to 99%. Ultrasonic plaque morphology was characterized as either heterogeneous (mixed hyperechoic, hypoechoic, and isoechoic) or homogeneous. RESULTS: Heterogeneous plaques were noted in 138 of 794 arteries with <50% stenosis, in 191 of 564 arteries with 50% to <60% stenosis, in 301 of 487 arteries with 60% to <70% stenosis, and in 496 of 615 arteries with 70% to 99% stenosis. The higher the degree of stenosis, the more likely it is to be associated with heterogeneous plaques. Heterogeneous plaques were present in 59% of the arteries with > or =50% stenoses versus 17% of the arteries with <50% stenoses, in 72% of the arteries with > or =60% stenoses versus 24% of the arteries with <60% stenosis, and in 80% of the arteries with > or =70% stenoses versus 34% of the arteries with <70% stenoses (P<0.0001 and odds ratios of 6.9, 8.1, and 8.0, respectively). Heterogeneous plaques were associated with an incidence of symptoms that was higher than that for homogeneous plaques for all grades of stenoses; percentages were, respectively, as follows: 68% versus 16% for <50% stenosis; 76% versus 21% for 50% to <60% stenosis; 79% versus 23% for 60% to <70% stenosis, and 86% versus 31% for > or =70% to 99% stenosis (P<0.0001 and odds ratios of 8.9, 11.9, 12.6, and 13.7, respectively). Heterogeneity of plaques was more positively correlated with symptoms than with any degree of stenosis (regardless of plaque structure). Eighty percent of all heterogeneous plaques were symptomatic versus 58% for all stenoses > or =50%, 68% for all stenoses > or =60%, and 75% for all stenoses > or =70% (P<0.0001, P<0.0001, and P=0.02, respectively). CONCLUSIONS: The higher the degree of carotid stenosis, the more likely it is to be associated with ultrasonic heterogeneous plaque and cerebrovascular symptoms. Heterogeneity of the plaque was more positively correlated with symptoms than with any degree of stenosis. These findings suggest that plaque heterogeneity should be considered in selecting patients for carotid endarterectomy.

Carotid Arteries↗

PubMed2006

Testing for genetic heterogeneity in the genome search meta-analysis method.

The Genome Search Meta-Analysis (GSMA) method is widely used to detect linkage by pooling results of previously published genome-wide linkage studies. The GSMA uses a non-parametric summed rank statistic in 30 cM bins of the genome. Zintzaras and Ioannidis ([2005] Genet. Epidemiol. 28:123-137) developed a method of testing for heterogeneity of evidence for linkage in the GSMA, with three heterogeneity statistics (Q, Ha, B). They implement two testing procedures, restricted versus unrestricted for the summed rank within the bin. We show here that the rank-unrestricted test provides a conservative test for high heterogeneity and liberal test for low heterogeneity in linked regions. The rank-restricted test should therefore be used, despite the extensive simulations needed. In a simulation study, we show that the power to detect heterogeneity is low. For 20 studies of affected sib pairs, simulated assuming linkage in all studies to a gene with sibling relative risk of 1.3, the power to detect low heterogeneity using the Q statistic was 14%. With linkage present in 50% of the studies (to a gene with sibling relative risk of 1.4), the Q heterogeneity statistic had power of 29% to detect high heterogeneity. The power to detect linkage using the summed rank was high in both of these situations, at 98% and 79%, respectively. Although testing for heterogeneity in the GSMA is of interest, the currently available method provides little additional information to that provided by the summed rank statistic.

Genetic Heterogeneity↗

PubMed2005

Evolution of intratumoral genetic heterogeneity during colorectal cancer progression.

Evolution of intratumoral genetic heterogeneity during colorectal tumor progression has not been investigated so far. Multiple sample areas in colorectal adenocarcinoma at early and advanced stages and in metastases were studied for the well-known genetic alterations: K-ras and p53 point mutations and loss of heterozygosity (LOH) on chromosomes 5q and 18q. In primary colorectal cancers (CRCs), intratumoral genetic heterogeneity was more often observed in early than in advanced stages, at 90 and 67%, respectively. All but one of the advanced CRCs were composed of one predominant clone and other minor clones, whereas no predominant clone has been identified in half of the early cancers. At the early stage, the last events that were produced, the p53 mutation and LOH of 18q, were also the most heterogeneous. At the advanced stage, the LOH of 5q and 18q were the most frequent heterogeneous events (67 and 58%, respectively). The intratumoral heterogeneity for mutations was significantly reduced, from the early to the advanced stages (from 60 to 20% for K-ras and from 70 to 20% for p53). On the other hand, a quasi absence of intratumoral genetic heterogeneity was observed for K-ras and p53 in distant metastasis. In conclusion, colorectal adenocarcinomas are characterized by marked intratumoral genetic heterogeneity. A reduction of the intratumoral genetic heterogeneity for point mutations and a relative stability of the heterogeneity for allelic losses indicate that, during the progression of CRC, clonal selection and chromosome instability continue, while an increase cannot be proven.

Colorectal Neoplasms↗

PubMed2025

Heterogeneity Analysis of Associations Involving the Large-Scale Online MindCrowd Survey Memory Test.

INTRODUCTION: Alzheimer's disease and related disorders (ADRDs), as well as general age-related cognitive decline, are known to be multifactorial with heterogeneous etiologies. Identifying and accommodating heterogeneity in any one ADRD-related data set can be pursued using different analytical techniques, each with different assumptions or purposes. For example, whereas a great deal of research has explored clustering individuals or variables that exhibit greater similarity in some way, little research has explored evidence for heterogeneity in the relationships between relevant outcomes, such as performance on a memory test, and risk factors such as environmental exposures, behaviors, or genetic factors among individuals. METHODS: We explored evidence of heterogeneity in the relationships between ability on a memory test, specifically the paired associate learning (PAL) test, and multiple social and demographic risk factors using the large MindCrowd study database (n > 90,000 individuals). We focused on mixtures of regression models but compared models assuming many interaction effects among independent variables as well as random effects. RESULTS: We ultimately find substantial evidence for heterogeneity and offer an intuitive explanation for it involving individual motivation for participating in the MindCrowd study. Basically, we argue that our mixture of regression model analysis results suggest that a smaller group of individuals (∼16%) likely participated in the MindCrowd study out of a concern for their cognitive abilities as they exhibit stronger and statistically significant negative associations between age, number of medications they are on, some ancestries, and the number correct on the PAL test. They also exhibit stronger positive associations between education and PAL test results in a dose-dependent manner suggesting that a "cognitive reserve" associated with greater education could benefit them. Analysis models assuming interaction terms and random effects suggested that other forms of heterogeneity in the relationships between variables exist in the data set, but their results do not carry with them the same intuitive explanation that the results of the mixture model analyses do. CONCLUSION: We find evidence for heterogeneity in the relationships between social and demographic variables and PAL test results in the large MindCrowd study database. This heterogeneity is likely due to individuals with and without concerns for their cognitive abilities participating in the study. We also find other types of evidence in the data set. Our results should motivate caution in the use of large epidemiological study or survey-oriented data sets to build predictive models of clinical or subclinical pathologies without exploring or accommodating heterogeneity. Our results also suggest that one should include questions about motivation to participate in large epidemiological studies since different motivations may impact important relationships between independent and dependent variables.

Humans↗

PubMed2004

The impact of population heterogeneity on risk estimation in genetic counseling.

BACKGROUND: Genetic counseling has been an important tool for evaluating and communicating disease susceptibility for decades, and it has been applied to predict risks for a wide class of hereditary disorders. Most diseases are complex in nature and are affected by multiple genes and environmental conditions; it is highly likely that DNA tests alone do not define all the genetic factors responsible for a disease, so that persons classified into the same risk group by DNA testing actually could have different disease susceptibilities. Ignorance of population heterogeneity may lead to biased risk estimates, whereas additional information on population heterogeneity may improve the precision of such estimates. METHODS: Although DNA tests are widely used, few studies have investigated the accuracy of the predicted risks. We examined the impact of population heterogeneity on predicted disease risks by simulation of three different heterogeneity scenarios and studied the precision and accuracy of the risks estimated from a logistic regression model that ignored population heterogeneity. Moreover, we also incorporated information about population heterogeneity into our original model and investigated the resulting improvement in the accuracy of risk estimation. RESULTS: We found that heterogeneity in one or more categories could lead to biased estimates not only in the "contaminated" categories but also in other homogeneous categories. Incorporating information about population heterogeneity into the original model greatly improved the accuracy of risk estimation. CONCLUSIONS: Our findings imply that without thorough knowledge about genetic basis of the disease, risks estimated from DNA tests may be misleading. Caution should be taken when evaluating the predicted risks obtained from genetic counseling. On the other hand, the improved accuracy of risk estimates after incorporating population heterogeneity information into the model did point out a promising direction for genetic counseling, since more and more new techniques are being invented and disease etiology is being better understood.

Bias↗