Number and Size Distribution of Colorectal Adenomas under the Multistage Clonal Expansion Model of Cancer

Colorectal cancer (CRC) is believed to arise from mutant stem cells in colonic crypts that undergo a well-characterized progression involving benign adenoma, the precursor to invasive carcinoma. Although a number of (epi)genetic events have been identified as drivers of this process, little is known about the dynamics involved in the stage-wise progression from the first appearance of an adenoma to its ultimate conversion to malignant cancer. By the time adenomas become endoscopically detectable (i.e., are in the range of 1–2 mm in diameter), adenomas are already comprised of hundreds of thousands of cells and may have been in existence for several years if not decades. Thus, a large fraction of adenomas may actually remain undetected during endoscopic screening and, at least in principle, could give rise to cancer before they are detected. It is therefore of importance to establish what fraction of adenomas is detectable, both as a function of when the colon is screened for neoplasia and as a function of the achievable detection limit. To this end, we have derived mathematical expressions for the detectable adenoma number and size distributions based on a recently developed stochastic model of CRC. Our results and illustrations using these expressions suggest (1) that screening efficacy is critically dependent on the detection threshold and implicit knowledge of the relevant stem cell fraction in adenomas, (2) that a large fraction of non-extinct adenomas remains likely undetected assuming plausible detection thresholds and cell division rates, and (3), under a realistic description of adenoma initiation, growth and progression to CRC, the empirical prevalence of adenomas is likely inflated with lesions that are not on the pathway to cancer

On Testing Dependence between Time to Failure and Cause of Failure when Causes of Failure Are Missing

The hypothesis of independence between the failure time and the cause of failure is studied by using the conditional probabilities of failure due to a specific cause given that there is no failure up to certain fixed time. In practice, there are situations when the failure times are available for all units but the causes of failures might be missing for some units. We propose tests based on U-statistics to test for independence of the failure time and the cause of failure in the competing risks model when all the causes of failure cannot be observed. The asymptotic distribution is normal in each case. Simulation studies look at power comparisons for the proposed tests for two families of distributions. The one-sided and the two-sided tests based on Kendall type statistic perform exceedingly well in detecting departures from independence

Accumulation of driver and passenger mutations during tumor progression

Major efforts to sequence cancer genomes are now occurring throughout the world. Though the emerging data from these studies are illuminating, their reconciliation with epidemiologic and clinical observations poses a major challenge. In the current study, we provide a novel mathematical model that begins to address this challenge. We model tumors as a discrete time branching process that starts with a single driver mutation and proceeds as each new driver mutation leads to a slightly increased rate of clonal expansion. Using the model, we observe tremendous variation in the rate of tumor development - providing an understanding of the heterogeneity in tumor sizes and development times that have been observed by epidemiologists and clinicians. Furthermore, the model provides a simple formula for the number of driver mutations as a function of the total number of mutations in the tumor. Finally, when applied to recent experimental data, the model allows us to calculate, for the first time, the actual selective advantage provided by typical somatic mutations in human tumors in situ. This selective advantage is surprisingly small, 0.005 +- 0.0005, and has major implications for experimental cancer research

A discrete MMAP for analysing the behaviour of a multi-state complex dynamic system subject to multiple events.

A complex multi-state system subject to different types of failures, repairable and/or nonrepairable, external shocks and preventive maintenance is modelled by considering a discrete Markovian arrival process with marked arrivals (D-MMAP). The internal performance of the system is composed of several degradation states partitioned into minor and major damage states according to the risk of failure. Random external events can produce failures throughout the system. If an external shock occurs, there may be an aggravation of the internal degradation, cumulative external damage or extreme external failure. The internal performance and the cumulative external damage are observed by random inspection. If major degradation is observed, the unit goes to the repair facility for preventive maintenance. If a repairable failure occurs then the system goes to corrective repair with different time distributions depending on the failure state. Time distributions for corrective repair and preventive maintenance depend on the failure state. Rewards and costs depending on the state at which the device failed or was inspected are introduced. The system is modelled and several measures of interest are built into transient and stationary regimes. A preventive maintenance policy is shown to determine the effectiveness of preventive maintenance and the optimum state of internal and cumulative external damage at which preventive maintenance should be taken into account. A numerical example is presented, revealing the efficacy of the model. Correlations between the numbers of different events over time and in non-overlapping intervals are calculated. The results are expressed in algorithmic-matrix form and are implemented computationally with Matlab.Junta de Andalucía, Spain, under the grant FQM307Ministerio de Economía y Competitividad, España, MTM2017-88708-PEuropean Regional Development Fund (ERDF

Universal asymptotic clone size distribution for general population growth

Deterministically growing (wild-type) populations which seed stochastically developing mutant clones have found an expanding number of applications from microbial populations to cancer. The special case of exponential wild-type population growth, usually termed the Luria-Delbr\"uck or Lea-Coulson model, is often assumed but seldom realistic. In this article we generalise this model to different types of wild-type population growth, with mutants evolving as a birth-death branching process. Our focus is on the size distribution of clones - that is the number of progeny of a founder mutant - which can be mapped to the total number of mutants. Exact expressions are derived for exponential, power-law and logistic population growth. Additionally for a large class of population growth we prove that the long time limit of the clone size distribution has a general two-parameter form, whose tail decays as a power-law. Considering metastases in cancer as the mutant clones, upon analysing a data-set of their size distribution, we indeed find that a power-law tail is more likely than an exponential one.Comment: 22 pages, 4 figures. To appear in the Bulletin of Mathematical Biology doi:10.1007/s11538-016-0221-

Systems biological and mechanistic modelling of radiation-induced cancer

This paper summarises the five presentations at the First International Workshop on Systems Radiation Biology that were concerned with mechanistic models for carcinogenesis. The mathematical description of various hypotheses about the carcinogenic process, and its comparison with available data is an example of systems biology. It promises better understanding of effects at the whole body level based on properties of cells and signalling mechanisms between them. Of these five presentations, three dealt with multistage carcinogenesis within the framework of stochastic multistage clonal expansion models, another presented a deterministic multistage model incorporating chromosomal aberrations and neoplastic transformation, and the last presented a model of DNA double-strand break repair pathways for second breast cancers following radiation therapy

Quasispecies Spatial Models for RNA Viruses with Different Replication Modes and Infection Strategies

Empirical observations and theoretical studies suggest that viruses may use different replication strategies to amplify their genomes, which impact the dynamics of mutation accumulation in viral populations and therefore, their fitness and virulence. Similarly, during natural infections, viruses replicate and infect cells that are rarely in suspension but spatially organized. Surprisingly, most quasispecies models of virus replication have ignored these two phenomena. In order to study these two viral characteristics, we have developed stochastic cellular automata models that simulate two different modes of replication (geometric vs stamping machine) for quasispecies replicating and spreading on a two-dimensional space. Furthermore, we explored these two replication models considering epistatic fitness landscapes (antagonistic vs synergistic) and different scenarios for cell-to-cell spread, one with free superinfection and another with superinfection inhibition. We found that the master sequences for populations replicating geometrically and with antagonistic fitness effects vanished at low critical mutation rates. By contrast, the highest critical mutation rate was observed for populations replicating geometrically but with a synergistic fitness landscape. Our simulations also showed that for stamping machine replication and antagonistic epistasis, a combination that appears to be common among plant viruses, populations further increased their robustness by inhibiting superinfection. We have also shown that the mode of replication strongly influenced the linkage between viral loci, which rapidly reached linkage equilibrium at increasing mutations for geometric replication. We also found that the strategy that minimized the time required to spread over the whole space was the stamping machine with antagonistic epistasis among mutations. Finally, our simulations revealed that the multiplicity of infection fluctuated but generically increased along time

Presence of tropical hydrophytes in relation to limnological parameters - a study of two freshwater ponds in Kolkata, India

The presence of different species of hydrophytes was investigated in relation to Secchi disk visibility, pH, dissolved oxygen, electrical conductivity, total Kjeldahl nitrogen, total phosphorus and chlorophyll-a concentration in two tropical ponds nearby Kolkata, India, during a three years period (June 1999 to May 2002). The dominant flora in the ponds namely, Alternanthera philoxeroides, Nymphoides hydrophylla, Lemna aequinoctialis, and Vallisneria spiralis were found to subsist over a wide amplitude of nutrient levels thereby showing their adaptability to highly eutrophic ecosystems, a common feature of the tropics. However, the presence of some minor species could be associated with a narrow range of specific limnological variables