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1.
Cancer Res Commun ; 3(1): 21-30, 2023 01 03.
Article in English | MEDLINE | ID: mdl-36685168

ABSTRACT

The goal of this project was to utilize mechanistic simulation to demonstrate a methodology that could determine drug combination dose schedules and dose intensities that would be most effective in eliminating multidrug resistant cancer cells in early-stage colon cancer. An agent-based model of cell dynamics in human colon crypts was calibrated using measurements of human biopsy specimens. Mutant cancer cells were simulated as cells that were resistant to each of two drugs when the drugs were used separately. The drugs, 5-flurouracil and sulindac, have different mechanisms of action. An artificial neural network was used to generate nearly two hundred thousand two-drug dose schedules. A high-performance computer simulated each dose schedule as a in silico clinical trial and evaluated each dose schedule for its efficiency to cure (eliminate) multidrug resistant cancer cells and its toxicity to the host, as indicated by continued crypt function. Among the dose schedules that were generated, 2430 dose schedules were found to cure all multidrug resistant mutants in each of the 50 simulated trials and retained colon crypt function. One dose schedule was optimal; it eliminated multidrug resistant cancer cells with the minimum toxicity and had a time schedule that would be practical for implementation in the clinic. These results demonstrate a procedure to identify which combination drug dose schedules could be most effective in eliminating drug resistant cancer cells. This was accomplished using a calibrated agent-based model of a human tissue, and a high-performance computer simulation of clinical trials.


Subject(s)
Colonic Neoplasms , Drug Resistance, Multiple , Humans , Computer Simulation , Drug Resistance, Neoplasm , Colonic Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effects
2.
Cancer Inform ; 21: 11769351211067697, 2022.
Article in English | MEDLINE | ID: mdl-35110963

ABSTRACT

Colon adenomas with proliferating mutant cells may progress to invasive carcinomas. Proliferation of cells in human colorectal tissue is circadian, greater in the interval 4 to 12 hours after midnight than 16 to 24 hours after midnight. We have tested the hypothesis that chemotherapy administered during the time of greater cell proliferation will be more effective than chemotherapy administered during the time of lesser proliferation. An agent-based computer model of cell proliferation in colon crypts was calibrated with measurements of cell numbers in human biopsy specimens. It was used to simulate cytotoxic chemotherapy of an early stage of colon cancer, adenomas with about 20% of mutant cells. Chemotherapy doses were scheduled at different 4-hour intervals during the 24-hour day, and repeated at weekly intervals. Chemotherapy administered at 4 to 8 hours after midnight cured mutant cells in 100% of 50 trials with an average time to cure of 7.82 days (s.e.m. = 0.99). In contrast, chemotherapy administered at 20 to 24 hours after midnight cured only 18% of 50 trials, with the average time to cure of 23.51 days (s.e.m. = 2.42). These simulation results suggest that clinical chemotherapy of early colon cancer may be more effective when given in the morning than later in the day.

3.
JCO Clin Cancer Inform ; 4: 514-520, 2020 06.
Article in English | MEDLINE | ID: mdl-32510974

ABSTRACT

PURPOSE: Adjuvant chemotherapy is used after surgery for stages II and III colorectal cancer to reduce recurrence. Nevertheless, recurrence may occur years later with the emergence of initially undetected minimal residual disease (MRD). Attempts to reduce recurrence by increasing the dose intensity and increasing the time of adjuvant therapy have been limited by the adverse effects of the recommended cytotoxic agents. The goals of this study were to suggest an alternative to the recommended cytotoxic agents and to determine optimal adjuvant therapy dose schedules that would reduce the percentage of recurrence at 5 years while retaining colon crypt function. METHODS: A total of 84,400 dose schedules with different duration, interval between doses, and intensity of treatment were simulated with a high-performance computer. Simulated treatments used the drug sulindac, which had previously been used in primary prevention. With appropriate dose schedules, it can induce apoptosis at the crypt lumen surface while retaining crypt function. We used a computer model of cell dynamics in colon crypts that had been calibrated with measurements of human biopsy specimens. Proliferating mutant cells were assumed to emerge from MRD within crypts. Simulated outcomes included the recurrence percentage at 5 years and the retention of crypt function. RESULTS: Optimal dose schedules were determined for adjuvant treatment of MRD that reduced the percentage of recurrence at 5 years of stages I, II, and III colon cancer to zero. CONCLUSION: A new adjuvant therapy for colon cancer based upon optimum dose schedules of intermittent apoptotic treatment may prevent the recurrence of colon cancer from MRD and avoid the adverse effects of cytotoxic treatments.


Subject(s)
Colonic Neoplasms , Neoplasm Recurrence, Local , Colonic Neoplasms/drug therapy , Computers , Humans , Neoplasm Recurrence, Local/prevention & control , Neoplasm, Residual
4.
Cancer Chemother Pharmacol ; 84(6): 1167-1178, 2019 12.
Article in English | MEDLINE | ID: mdl-31512030

ABSTRACT

PURPOSE: We report on a statistical method for grouping anti-cancer drugs (GRAD) in single mouse trials (SMT). The method assigns candidate drugs into groups that inhibit or do not inhibit tumor growth in patient-derived xenografts (PDX). It determines the statistical significance of the group assignments without replicate trials of each drug. METHODS: The GRAD method applies a longitudinal finite mixture model, implemented in the statistical package PROC TRAJ, to analyze a mixture of tumor growth curves for portions of the same tumor in different mice, each single mouse exposed to a different drug. Each drug is classified into an inhibitory or non-inhibitory group. There are several advantages to the GRAD method for SMT. It determines that probability that the grouping is correct, uses the entire longitudinal tumor growth curve data for each drug treatment, can fit different shape growth curves, accounts for missing growth curve data, and accommodates growth curves of different time periods. RESULTS: We analyzed data for 22 drugs for 18 human colorectal tumors provided by researchers in a previous publication. The GRAD method identified 18 drugs that were inhibitory against at least one tumor, and 10 tumors for which there was at least one inhibitory drug. Analysis of simulated data indicated that the GRAD method has a sensitivity of 84% and a specificity of 98%. CONCLUSION: A statistical method, GRAD, can group anti-cancer drugs into those that are inhibitory and those that are non-inhibitory in single mouse trials and provide probabilities that the grouping is correct.


Subject(s)
Antineoplastic Agents/pharmacology , Colorectal Neoplasms/drug therapy , Data Interpretation, Statistical , Tumor Burden/drug effects , Animals , Antineoplastic Agents/therapeutic use , Colorectal Neoplasms/pathology , Feasibility Studies , Humans , Mice , Sensitivity and Specificity , Treatment Outcome , Xenograft Model Antitumor Assays
5.
Cancer Inform ; 18: 1176935118822804, 2019.
Article in English | MEDLINE | ID: mdl-30675100

ABSTRACT

Cancer chemotherapy dose schedules are conventionally applied intermittently, with dose duration of the order of hours, intervals between doses of days or weeks, and cycles repeated for weeks. The large number of possible combinations of values of duration, interval, and lethality has been an impediment to empirically determine the optimal set of treatment conditions. The purpose of this project was to determine the set of parameters for duration, interval, and lethality that would be most effective for treating early colon cancer. An agent-based computer model that simulated cell proliferation kinetics in normal human colon crypts was calibrated with measurements of human biopsy specimens. Mutant cells were simulated as proliferating and forming an adenoma, or dying if treated with cytotoxic chemotherapy. Using a high-performance computer, a total of 28 800 different parameter sets of duration, interval, and lethality were simulated. The effect of each parameter set on the stability of colon crypts, the time to cure a crypt of mutant cells, and the accumulated dose was determined. Of the 28 800 parameter sets, 434 parameter sets were effective in curing the crypts of mutant cells before they could form an adenoma and allowed the crypt normal cell dynamics to recover to pretreatment levels. A group of 14 similar parameter sets produced a minimal time to cure mutant cells. A different group of nine similar parameter sets produced the least accumulated dose. These parameter sets may be considered as candidate dose schedules to guide clinical trials for early colon cancer.

6.
J Theor Biol ; 429: 190-203, 2017 09 21.
Article in English | MEDLINE | ID: mdl-28669884

ABSTRACT

The question of stem cell control is at the center of our understanding of tissue functioning, both in healthy and cancerous conditions. It is well accepted that cellular fate decisions (such as divisions, differentiation, apoptosis) are orchestrated by a network of regulatory signals emitted by different cell populations in the lineage and the surrounding tissue. The exact regulatory network that governs stem cell lineages in a given tissue is usually unknown. Here we propose an algorithm to identify a set of candidate control networks that are compatible with (a) measured means and variances of cell populations in different compartments, (b) qualitative information on cell population dynamics, such as the existence of local controls and oscillatory reaction of the system to population size perturbations, and (c) statistics of correlations between cell numbers in different compartments. Using the example of human colon crypts, where lineages are comprised of stem cells, transit amplifying cells, and differentiated cells, we start with a theoretically known set of 32 smallest control networks compatible with tissue stability. Utilizing near-equilibrium stochastic calculus of stem cells developed earlier, we apply a series of tests, where we compare the networks' expected behavior with the observations. This allows us to exclude most of the networks, until only three, very similar, candidate networks remain, which are most compatible with the measurements. This work demonstrates how theoretical analysis of control networks combined with only static biological data can shed light onto the inner workings of stem cell lineages, in the absence of direct experimental assessment of regulatory signaling mechanisms. The resulting candidate networks are dominated by negative control loops and possess the following properties: (1) stem cell division decisions are negatively controlled by the stem cell population, (2) stem cell differentiation decisions are negatively controlled by the transit amplifying cell population.


Subject(s)
Cell Lineage , Colon/cytology , Gene Regulatory Networks/physiology , Stem Cells/cytology , Animals , Cell Differentiation , Cell Division , Humans , Models, Biological
7.
Cancer Chemother Pharmacol ; 79(5): 889-898, 2017 May.
Article in English | MEDLINE | ID: mdl-28343282

ABSTRACT

PURPOSE: The effectiveness of cancer chemotherapy is limited by intra-tumor heterogeneity, the emergence of spontaneous and induced drug-resistant mutant subclones, and the maximum dose to which normal tissues can be exposed without adverse side effects. The goal of this project was to determine if intermittent schedules of the maximum dose that allows colon crypt maintenance could overcome these limitations, specifically by eliminating mixtures of drug-resistant mutants from heterogeneous early colon adenomas while maintaining colon crypt function. METHODS: A computer model of cell dynamics in human colon crypts was calibrated with measurements of human biopsy specimens. The model allowed simulation of continuous and intermittent dose schedules of a cytotoxic chemotherapeutic drug, as well as the drug's effect on the elimination of mutant cells and the maintenance of crypt function. RESULTS: Colon crypts can tolerate a tenfold greater intermittent dose than constant dose. This allows elimination of a mixture of relatively drug-sensitive and drug-resistant mutant subclones from heterogeneous colon crypts. Mutants can be eliminated whether they arise spontaneously or are induced by the cytotoxic drug. CONCLUSIONS: An intermittent dose, at the maximum that allows colon crypt maintenance, can be effective in eliminating a heterogeneous mixture of mutant subclones before they fill the crypt and form an adenoma.


Subject(s)
Adenoma/drug therapy , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Colonic Neoplasms/drug therapy , Aberrant Crypt Foci , Calibration , Computer Simulation , Disease Progression , Drug Administration Schedule , Drug Resistance, Neoplasm , Humans , Mutation
8.
Theor Biol Med Model ; 10: 66, 2013 Nov 18.
Article in English | MEDLINE | ID: mdl-24245614

ABSTRACT

BACKGROUND: Normal colon crypts consist of stem cells, proliferating cells, and differentiated cells. Abnormal rates of proliferation and differentiation can initiate colon cancer. We have measured the variation in the number of each of these cell types in multiple crypts in normal human biopsy specimens. This has provided the opportunity to produce a calibrated computational model that simulates cell dynamics in normal human crypts, and by changing model parameter values, to simulate the initiation and treatment of colon cancer. RESULTS: An agent-based model of stochastic cell dynamics in human colon crypts was developed in the multi-platform open-source application NetLogo. It was assumed that each cell's probability of proliferation and probability of death is determined by its position in two gradients along the crypt axis, a divide gradient and in a die gradient. A cell's type is not intrinsic, but rather is determined by its position in the divide gradient. Cell types are dynamic, plastic, and inter-convertible. Parameter values were determined for the shape of each of the gradients, and for a cell's response to the gradients. This was done by parameter sweeps that indicated the values that reproduced the measured number and variation of each cell type, and produced quasi-stationary stochastic dynamics. The behavior of the model was verified by its ability to reproduce the experimentally observed monocolonal conversion by neutral drift, the formation of adenomas resulting from mutations either at the top or bottom of the crypt, and by the robust ability of crypts to recover from perturbation by cytotoxic agents. One use of the virtual crypt model was demonstrated by evaluating different cancer chemotherapy and radiation scheduling protocols. CONCLUSIONS: A virtual crypt has been developed that simulates the quasi-stationary stochastic cell dynamics of normal human colon crypts. It is unique in that it has been calibrated with measurements of human biopsy specimens, and it can simulate the variation of cell types in addition to the average number of each cell type. The utility of the model was demonstrated with in silico experiments that evaluated cancer therapy protocols. The model is available for others to conduct additional experiments.


Subject(s)
Colon/pathology , Computer Simulation , Models, Biological , Biopsy , Calibration , Cell Count , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Feedback, Physiological , Humans , Ki-67 Antigen/metabolism , Mutation , Reproducibility of Results , Stochastic Processes
9.
Cancer Clin Oncol ; 1(1): 52-64, 2012.
Article in English | MEDLINE | ID: mdl-26322145

ABSTRACT

p53 protein detected immunohistochemically has not been accepted as a biomarker for breast cancer patients because of disparate reports of the relationship between the amount of p53 protein detected and patient survival. The purpose of this study was to determine experimental conditions and methods of data analysis for which p53 stain intensity could be prognostic for survival of young breast cancer patients. A tissue microarray of specimens from 93 patients was stained with anti-p53 antibody, and stain intensity measured with a computer-aided image analysis system. A cut-point at one standard deviation below the mean of the distribution of p53 stain intensity separated patients into two groups with significantly different survival. These results were confirmed by Quantitative Nuclear Grade determined by DNA-specific Feulgen staining. P53 provided information beyond ER and PR status. Therefore, under the conditions reported here, p53 protein can be an effective prognostic factor for young breast cancer patients.

10.
Cancer Inform ; 9: 209-16, 2010 Sep 07.
Article in English | MEDLINE | ID: mdl-20981137

ABSTRACT

PURPOSE: Nuclear grade of breast DCIS is considered during patient management decision-making although it may have only a modest prognostic association with therapeutic outcome. We hypothesized that visual inspection may miss substantive differences in nuclei classified as having the same nuclear grade. To test this hypothesis, we measured subvisual nuclear features by quantitative image cytometry for nuclei with the same grade, and tested for statistical differences in these features. EXPERIMENTAL DESIGN AND STATISTICAL ANALYSIS: Thirty-nine nuclear digital image features of about 100 nuclei were measured in digital images of H&E stained slides of 81 breast biopsy specimens. One field with at least 5 ducts was evaluated for each patient. We compared features of nuclei with the same grade in multiple ducts of the same patient with ANOVA (or Welch test), and compared features of nuclei with the same grade in two ducts of different patients using 2-sided t-tests (P ≤ 0.05). Also, we compared image features for nuclei in patients with single grade to those with the same grade in patients with multiple grades using t-tests. RESULTS: Statistically significant differences were detected in nuclear features between ducts with the same nuclear grade, both in different ducts of the same patient, and between ducts in different patients with DCIS of more than one grade. CONCLUSION: Nuclei in ducts visually described as having the same nuclear grade had significantly different subvisual digital image features. These subvisual differences may be considered additional manifestations of heterogeneity over and above differences that can be observed microscopically. This heterogeneity may explain the inconsistency of nuclear grading as a prognostic factor.

11.
Biomed Inform Insights ; 2: 11-18, 2009 Jan 01.
Article in English | MEDLINE | ID: mdl-20191105

ABSTRACT

Information about tumors is usually obtained from a single assessment of a tumor sample, performed at some point in the course of the development and progression of the tumor, with patient characteristics being surrogates for natural history context. Differences between cells within individual tumors (intratumor heterogeneity) and between tumors of different patients (intertumor heterogeneity) may mean that a small sample is not representative of the tumor as a whole, particularly for solid tumors which are the focus of this paper. This issue is of increasing importance as high-throughput technologies generate large multi-feature data sets in the areas of genomics, proteomics, and image analysis. Three potential pitfalls in statistical analysis are discussed (sampling, cut-points, and validation) and suggestions are made about how to avoid these pitfalls.

12.
Transl Oncol ; 1(4): 158-64, 2008 Dec.
Article in English | MEDLINE | ID: mdl-19043526

ABSTRACT

We propose that there is an opportunity to devise new cancer therapies based on the recognition that tumors have properties of ecological systems. Traditionally, localized treatment has targeted the cancer cells directly by removing them (surgery) or killing them (chemotherapy and radiation). These modes of therapy have not always been effective because many tumors recur after these therapies, either because not all of the cells are killed (local recurrence) or because the cancer cells had already escaped the primary tumor environment (distant recurrence). There has been an increasing recognition that the tumor microenvironment contains host noncancer cells in addition to cancer cells, interacting in a dynamic fashion over time. The cancer cells compete and/or cooperate with nontumor cells, and the cancer cells may compete and/or cooperate with each other. It has been demonstrated that these interactions can alter the genotype and phenotype of the host cells as well as the cancer cells. The interaction of these cancer and host cells to remodel the normal host organ microenvironment may best be conceptualized as an evolving ecosystem. In classic terms, an ecosystem describes the physical and biological components of an environment in relation to each other as a unit. Here, we review some properties of tumor microenvironments and ecological systems and indicate similarities between them. We propose that describing tumors as ecological systems defines new opportunities for novel cancer therapies and use the development of prostate cancer metastases as an example. We refer to this as "ecological therapy" for cancer.

13.
Cancer Inform ; 6: 99-109, 2008.
Article in English | MEDLINE | ID: mdl-18779878

ABSTRACT

BACKGROUND: Nuclear grade has been associated with breast DCIS recurrence and progression to invasive carcinoma; however, our previous study of a cohort of patients with breast DCIS did not find such an association with outcome. Fifty percent of patients had heterogeneous DCIS with more than one nuclear grade. The aim of the current study was to investigate the effect of quantitative nuclear features assessed with digital image analysis on ipsilateral DCIS recurrence. METHODS: Hematoxylin and eosin stained slides for a cohort of 80 patients with primary breast DCIS were reviewed and two fields with representative grade (or grades) were identified by a Pathologist and simultaneously used for acquisition of digital images for each field. Van Nuys worst nuclear grade was assigned, as was predominant grade, and heterogeneous grading when present. Patients were grouped by heterogeneity of their nuclear grade: Group A: nuclear grade 1 only, nuclear grades 1 and 2, or nuclear grade 2 only (32 patients), Group B: nuclear grades 1, 2 and 3, or nuclear grades 2 and 3 (31 patients), Group 3: nuclear grade 3 only (17 patients). Nuclear fine structure was assessed by software which captured thirty-nine nuclear feature values describing nuclear morphometry, densitometry, and texture. Step-wise forward Cox regressions were performed with previous clinical and pathologic factors, and the new image analysis features. RESULTS: Duplicate measurements were similar for 89.7% to 97.4% of assessed image features. The rate of correct classification of nuclear grading with digital image analysis features was similar in the two fields, and pooled assessment across both fields. In the pooled assessment, a discriminant function with one nuclear morphometric and one texture feature was significantly (p = 0.001) associated with nuclear grading, and provided correct jackknifed classification of a patient's nuclear grade for Group A (78.1%), Group B (48.4%), and Group C (70.6%). The factors significantly associated with DCIS recurrence were those previously found, type of initial presentation (p = 0.03) and amount of parenchymal involvement (p = 0.05), along with the morphometry image feature of ellipticity (p = 0.04). CONCLUSION: Analysis of nuclear features measured by image cytometry may contribute to the classification and prognosis of breast DCIS patients with more than one nuclear grade.

14.
BMC Cancer ; 7: 174, 2007 Sep 10.
Article in English | MEDLINE | ID: mdl-17845726

ABSTRACT

BACKGROUND: Previously, 50% of patients with breast ductal carcinoma in situ (DCIS) had more than one nuclear grade, and neither worst nor predominant nuclear grade was significantly associated with development of invasive carcinoma. Here, we used image analysis in addition to histologic evaluation to determine if quantification of nuclear features could provide additional prognostic information and hence impact prognostic assessments. METHODS: Nuclear image features were extracted from about 200 nuclei of each of 80 patients with DCIS who underwent lumpectomy alone, and received no adjuvant systemic therapy. Nuclear images were obtained from 20 representative nuclei per duct, from each of a group of 5 ducts, in two separate fields, for 10 ducts. Reproducibility of image analysis features was determined, as was the ability of features to discriminate between nuclear grades. Patient information was available about clinical factors (age and method of DCIS detection), pathologic factors (DCIS size, nuclear grade, margin size, and amount of parenchymal involvement), and 39 image features (morphology, densitometry, and texture). The prognostic effects of these factors and features on the development of invasive breast cancer were examined with Cox step-wise multivariate regression. RESULTS: Duplicate measurements were similar for 89.7% to 97.4% of assessed image features. For the pooled assessment with approximately 200 nuclei per patient, a discriminant function with one densitometric and two texture features was significantly (p < 0.001) associated with nuclear grading, and provided 78.8% correct jackknifed classification of a patient's nuclear grade. In multivariate assessments, image analysis nuclear features had significant prognostic associations (p

Subject(s)
Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/pathology , Cell Nucleus/pathology , Breast Neoplasms/mortality , Carcinoma, Ductal, Breast/mortality , Cell Nucleus Shape , Female , Humans , Image Processing, Computer-Assisted , Kaplan-Meier Estimate , Neoplasm Invasiveness/pathology , Neoplasm Recurrence, Local/pathology , Prognosis
16.
Proc Natl Acad Sci U S A ; 103(36): 13474-9, 2006 Sep 05.
Article in English | MEDLINE | ID: mdl-16938860

ABSTRACT

The evolution of cooperation has a well established theoretical framework based on game theory. This approach has made valuable contributions to a wide variety of disciplines, including political science, economics, and evolutionary biology. Existing cancer theory suggests that individual clones of cancer cells evolve independently from one another, acquiring all of the genetic traits or hallmarks necessary to form a malignant tumor. It is also now recognized that tumors are heterotypic, with cancer cells interacting with normal stromal cells within the tissue microenvironment, including endothelial, stromal, and nerve cells. This tumor cell-stromal cell interaction in itself is a form of commensalism, because it has been demonstrated that these nonmalignant cells support and even enable tumor growth. Here, we add to this theory by regarding tumor cells as game players whose interactions help to determine their Darwinian fitness. We marshal evidence that tumor cells overcome certain host defenses by means of diffusible products. Our original contribution is to raise the possibility that two nearby cells can protect each other from a set of host defenses that neither could survive alone. Cooperation can evolve as by-product mutualism among genetically diverse tumor cells. Our hypothesis supplements, but does not supplant, the traditional view of carcinogenesis in which one clonal population of cells develops all of the necessary genetic traits independently to form a tumor. Cooperation through the sharing of diffusible products raises new questions about tumorigenesis and has implications for understanding observed phenomena, designing new experiments, and developing new therapeutic approaches.


Subject(s)
Biological Evolution , Models, Biological , Neoplasms/pathology , Cell Transformation, Neoplastic , Game Theory , Humans , Neoplasms/etiology , Neoplasms/genetics
17.
Breast Cancer Res ; 8(4): R41, 2006.
Article in English | MEDLINE | ID: mdl-16859500

ABSTRACT

INTRODUCTION: The potential of applying data analysis tools to microarray data for diagnosis and prognosis is illustrated on the recent breast cancer dataset of van 't Veer and coworkers. We re-examine that dataset using the novel technique of logical analysis of data (LAD), with the double objective of discovering patterns characteristic for cases with good or poor outcome, using them for accurate and justifiable predictions; and deriving novel information about the role of genes, the existence of special classes of cases, and other factors. METHOD: Data were analyzed using the combinatorics and optimization-based method of LAD, recently shown to provide highly accurate diagnostic and prognostic systems in cardiology, cancer proteomics, hematology, pulmonology, and other disciplines. RESULTS: LAD identified a subset of 17 of the 25,000 genes, capable of fully distinguishing between patients with poor, respectively good prognoses. An extensive list of 'patterns' or 'combinatorial biomarkers' (that is, combinations of genes and limitations on their expression levels) was generated, and 40 patterns were used to create a prognostic system, shown to have 100% and 92.9% weighted accuracy on the training and test sets, respectively. The prognostic system uses fewer genes than other methods, and has similar or better accuracy than those reported in other studies. Out of the 17 genes identified by LAD, three (respectively, five) were shown to play a significant role in determining poor (respectively, good) prognosis. Two new classes of patients (described by similar sets of covering patterns, gene expression ranges, and clinical features) were discovered. As a by-product of the study, it is shown that the training and the test sets of van 't Veer have differing characteristics. CONCLUSION: The study shows that LAD provides an accurate and fully explanatory prognostic system for breast cancer using genomic data (that is, a system that, in addition to predicting good or poor prognosis, provides an individualized explanation of the reasons for that prognosis for each patient). Moreover, the LAD model provides valuable insights into the roles of individual and combinatorial biomarkers, allows the discovery of new classes of patients, and generates a vast library of biomedical research hypotheses.


Subject(s)
Breast Neoplasms/epidemiology , Breast Neoplasms/genetics , Gene Expression Profiling/statistics & numerical data , Female , Genetic Markers , Humans , Models, Genetic , Prognosis , Statistics as Topic
18.
J Theor Biol ; 232(2): 179-89, 2005 Jan 21.
Article in English | MEDLINE | ID: mdl-15530488

ABSTRACT

To better understand the progression of heterogeneous breast cancers, four models of progession pathways have been evaluated. The models describe the progression through the grades of ductal carcinoma in situ (DCIS) 1, 2, and 3, and through the grades of invasive ductal carcinoma (IDC) 1, 2, and 3. The first three pathways, termed linear, nonlinear, and branched, describe DCIS as a progenitor of IDC, and grades of DCIS progressing into grades of IDC. The fourth pathway, termed parallel, describes DCIS and IDC as diverging from a common progenitor and progressing through grades in parallel. The best transition rates for the linear, nonlinear, and branched pathways were sought using a random search in combination with a directed search based on the Nelder-Mead simplex method. Parameter values for the parallel pathway were determined with heuristic graphs. Results of computer simulation were compared with clinically observed frequencies of grades of DCIS and grades of IDC that were reported to occur together in heterogeneous tumors. Each of the four pathways could simulate frequencies that resembled, to varying degrees, the clinical observations. The parallel pathway produced the best correspondence with clinical observations. These results quantify the traditional descriptions in which grades of DCIS are the progenitors of grades of IDC. The results also raise the alternative possibility that, in some tumors with both components, DCIS and IDC may have diverged from a common progenitor.


Subject(s)
Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/pathology , Carcinoma, Intraductal, Noninfiltrating/pathology , Algorithms , Computer Simulation , Disease Progression , Female , Humans , Models, Biological , Neoplasm Invasiveness , Neoplastic Stem Cells/pathology
19.
Biomed Pharmacother ; 58 Suppl 1: S140-4, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15754853

ABSTRACT

The aim of this study was to assess components of variation in nocturia and to determine any putative geomagnetic influence. A 54-year old man with benign prostatic hyperplasia had recorded for about 4 years the number of times he awoke each night to urinate. The data have been reanalyzed for chronomics, the mapping of time structures (chronomes), involving the computation of least squares spectra of the urinary record and of environmental variables recorded during the same 4-year span. In addition to the previously reported monthly variation, other periodicities have been documented, including two separate components with periods of one week and of a near-week. The precise 7-day period may be a mainly exogenous resonance with external influences such as a weekly social schedule, whereas the near-week may be a partial resonance with natural changes in geomagnetics, reflecting in part changes in other non-photic natural environmental factors.


Subject(s)
Polyuria/etiology , Biological Clocks , Humans , Male , Periodicity , Polyuria/complications , Polyuria/epidemiology , Prostatic Hyperplasia/complications , Prostatic Hyperplasia/diagnosis , Risk Factors
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