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Wayne S Kendal

Publications and source records attributed to Wayne S Kendal.

14 recordsLinked to original sources
PubMed2006

Scale invariant correlations between genes and SNPs on Human chromosome 1 reveal potential evolutionary mechanisms.

The local density of gene structures and single nucleotide polymorphisms (SNPs) along human chromosomes appears inhomogeneous. In chromosome 1, the density patterns from both these elements are shown here to exhibit similar scale invariant clustering, as well as long-ranged and scale invariant auto- and cross-correlations. The local densities of these elements sites can be accurately represented by the scale invariant exponential dispersion models, a group of stochastic models that act as limiting distributions for a wide range of generalized linear models. The scale invariant Poisson-gamma (PG) distribution is the most applicable of these models, since it describes the above findings and it lends itself to a stochastic mechanism for the accumulation of segmental chromosomal changes. This PG model describes the summation of neutral chromosomal mutations, deletions, rearrangements and recombinations, within chromosomal segments that are distinguished by their evolutionary genealogies. Scale invariance is a necessary property if such a description is to remain valid at different measurement scales. The observed density patterns, and proposed model, presumably represent the convergent summation of multiple stochastic processes within the evolutionary history of the chromosome.

Chromosomes, Human, Pair 1↗
PubMed2006

Prostatic irradiation is not associated with any measurable increase in the risk of subsequent rectal cancer.

PURPOSE: To investigate a putative increased risk of rectal cancer subsequent to prostatic radiotherapy. METHODS AND MATERIALS: In an analysis of the Surveillance, Epidemiology, and End Results registry, we compared men who had radiotherapy for prostatic carcinoma with those treated surgically and those treated with neither modality. Kaplan-Meier analyses for the time to failure from rectal cancer were performed between age-matched subgroups of the three cohorts. Cox proportional hazards analyses were performed to ascertain what influences might affect the incidence of subsequent rectal cancer. RESULTS: In all, 33,831 men were irradiated, 167,607 were treated surgically, and 36,335 received neither modality. Rectal cancers developed in 243 (0.7%) of those irradiated (mean age, 70.7 years), 578 (0.3%) of those treated surgically (68.7 years), and 227 (0.8%) of those treated with neither modality (74.2 years). When age effects and the differences between the surgical and untreated cohorts were controlled for, we were unable to demonstrate any significant increased incidence of rectal cancer in men irradiated for prostatic cancer. CONCLUSIONS: An increased frequency of rectal cancer after prostatic irradiation, apparent on crude analysis, could be attributed to age confounding and other unmeasured confounders associated with prostate cancer treatment and rectal cancer risk.

Age Factors↗
PubMed2006

The number distribution for involved lymph nodes in cancer.

The number of involved lymph nodes exhibits considerable heterogeneity within populations. Here, the implications of population heterogeneity are explored with respect to the kinematics of nodal metastases. Data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program for 224656 breast, 12404 gastric, 18015 rectal, 4117 cervical and 2443 laryngeal cancers as well as 9118 melanomas were used to construct frequency distributions for the number of involved nodes which were then fitted to the negative binomial distribution. The negative binomial distribution described the heterogeneity in nodal involvement well. The patterns of nodal involvement can be explained by either of two models: one where involved nodes could seed further nodal metastases, the other where the number of nodal metastases in any individual was randomly distributed, with the deviations between patients accounted for by population heterogeneity. Since the number of sampled nodes similarly approximated a negative binomial distribution, random involvement with superimposed population heterogeneity would more credibly explain both sets of observations.

Binomial Distribution↗
PubMed2006

Lymph node-based prognostics: limitations with individualized cancer treatment.

OBJECTIVES: Clinicians will commonly individualize adjuvant cancer therapy, on the basis of the number of involved lymph nodes and other clinicopathological factors, under the assumption that despite the expected statistical variability of such data one can nonetheless garner useful information for the individual case. Here the scientific basis of this assumption will be examined. METHODS: Survival data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program for 19,107 breast, 4,234 gastric, and 4,058 rectal cancers were studied with Kaplan-Meier estimates and Cox proportionate hazard models. The minimal sample size required to discriminate between high and low-risk groups was determined from the hazard ratios between various comparative groups, and their respective frequencies. RESULTS: The number of involved nodes was the strongest prognostic factor for all 3 cancers, followed by tumor diameter and grade. Discrimination between high and low-risk nodal prognostic groups required samples of 30 to 200 cases, depending on the prognostics used and the specific tumor, to attain a two-sided alpha of 0.05% with 90% power. At the individual level such prognostications therefore were uninformative. CONCLUSIONS: Clinicopathological prognostics based upon the number of involved lymph nodes are subject to population heterogeneity that limits their application to large samples. At the individual level, these prognostics appear more spurious than useful. The use of such prognostics to tailor cancer treatment to individuals should be considered a specious practice; instead a more categorical approach, based on the results of randomized trials, should be used.

Breast Neoplasms↗
PubMed2005

Chance mechanisms affecting the burden of metastases.

BACKGROUND: The burden of cancer metastases within an individual is commonly used to clinically characterize a tumor's biological behavior. Assessments like these implicitly assume that spurious effects can be discounted. Here the influence of chance on the burden of metastasis is studied to determine whether or not this assumption is valid. METHODS: Monte Carlo simulations were performed to estimate tumor burdens sustained by individuals with cancer, based upon empirically derived and validated models for the number and size distributions of metastases. Factors related to the intrinsic metastatic potential of tumors and their host microenvironments were kept constant, to more clearly demonstrate the contribution from chance. RESULTS: Under otherwise identical conditions, both the simulated numbers and the sizes of metastases were highly variable. Comparable individuals could sustain anywhere from no metastases to scores of metastases, and the sizes of the metastases ranged from microscopic to macroscopic. Despite the marked variability in the number and sizes of the metastases, their respective growth times were rather more narrowly distributed. In such situations multiple occult metastases could develop into fully overt lesions within a comparatively short time period. CONCLUSION: Chance can have a major effect on the burden of metastases. Random variability can be so great as to make individual assessments of tumor biology unreliable, yet constrained enough to lead to the apparently simultaneous appearance of multiple overt metastases.

Animals↗
PubMed2005

Large-scale genomic correlations in Arabidopsis thaliana relate to chromosomal structure.

BACKGROUND: The chromosomes of the plant Arabidopsis thaliana contain various genomic elements, distributed with appreciable spatial heterogeneity. Clustering of and/or correlations between these elements presumably should reflect underlying functional or structural factors. We studied the positional density fluctuations and correlations between genes, indels, single nucleotide polymorphisms (SNPs), retrotransposons, 180 bp tandem repeats, and conserved centromeric sequences (CCSs) in Arabidopsis in order to elucidate any patterns and possible responsible factors for their genomic distributions. RESULTS: The spatial distributions of all these elements obeyed a common pattern: the density profiles of each element within chromosomes exhibited low-frequency fluctuations indicative of regional clustering, and the individual density profiles tended to correlate with each other at large measurement scales. This pattern could be attributed to the influence of major chromosomal structures, such as centromeres. At smaller scales the correlations tended to weaken -- evidence that localized cis-interactions between the different elements had a comparatively minor, if any, influence on their placement. CONCLUSION: The conventional notion that retrotransposon insertion sites are strongly influenced by cis-interactions was not supported by these observations. Moreover, we would propose that large-scale chromosomal structure has a dominant influence on the intrachromosomal distributions of genomic elements, and provides for an additional shared hierarchy of genomic organization within Arabidopsis.

Arabidopsis↗
PubMed2005

Statistical kinematics of axillary nodal metastases in breast carcinoma.

The number of involved lymph nodes in individuals with breast cancer is highly variable, and of both prognostic and therapeutic importance. A statistical description for the frequency distribution of the numbers of involved nodes in an affected population could potentially reveal mechanisms of axillary metastasis, and eventually facilitate predictive models for tumor control and axillary sampling. A meta-analysis of 15 studies involving 24,757 axillary dissections was performed, including conventional dissections, sentinel node dissections and studies of occult metastases. Frequency histograms for the numbers of involved axillary lymph nodes from the populations were tested for clustering and they were fitted, as a first approximation, to a negative binomial distribution. Although the number of involved nodes per individual was quite variable, some individuals sustained more involved nodes than could be expected from a random (Poisson) distribution. The negative binomial distribution, however, provided acceptable descriptions for the distributions of involved nodes in all populations studied. Two mechanisms could explain these observations: (1) an apparent contagion model, where involved nodes seeded further nodal metastases, and (2) a spurious contagion model where the number of involved nodes per individual was randomly (Poisson) distributed and population heterogeneity accounted for the more severe cases. Both models were consistent with the hypothesis that the nodal metastasis is a chance event, with the probability of involvement greatest for nodes contiguous to the primary tumor and proportioned by lymphatic flow.

Biomechanical Phenomena↗
PubMed2004

A scale invariant clustering of genes on human chromosome 7.

BACKGROUND: Vertebrate genes often appear to cluster within the background of nontranscribed genomic DNA. Here an analysis of the physical distribution of gene structures on human chromosome 7 was performed to confirm the presence of clustering, and to elucidate possible underlying statistical and biological mechanisms. RESULTS: Clustering of genes was confirmed by virtue of a variance of the number of genes per unit physical length that exceeded the respective mean. Further evidence for clustering came from a power function relationship between the variance and mean that possessed an exponent of 1.51. This power function implied that the spatial distribution of genes on chromosome 7 was scale invariant, and that the underlying statistical distribution had a Poisson-gamma (PG) form. A PG distribution for the spatial scattering of genes was validated by stringent comparisons of both the predicted variance to mean power function and its cumulative distribution function to data derived from chromosome 7. CONCLUSION: The PG distribution was consistent with at least two different biological models: In the microrearrangement model, the number of genes per unit length of chromosome represented the contribution of a random number of smaller chromosomal segments that had originated by random breakage and reconstruction of more primitive chromosomes. Each of these smaller segments would have necessarily contained (on average) a gamma distributed number of genes. In the gene cluster model, genes would be scattered randomly to begin with. Over evolutionary timescales, tandem duplication, mutation, insertion, deletion and rearrangement could act at these gene sites through a stochastic birth death and immigration process to yield a PG distribution. On the basis of the gene position data alone it was not possible to identify the biological model which best explained the observed clustering. However, the underlying PG statistical model implicated neutral evolutionary mechanisms as the basis for this clustering.

Algorithms↗
PubMed2004

Comparison of the X-radiation, drug and ultraviolet-radiation responses of clones isolated from a human colorectal tumor cell line.

We isolated several clones with a wide range of responses to X radiation from an unirradiated human colorectal (HCT 116) tumor cell line. The responses of one of these clones (HCT116-Clone10) and nine other clones to either fractionated or acute (i.e. single, nonfractionated doses) X irradiation in vitro was similar to that of the parental cell line. By contrast, after the same types of treatment, another clone (HCT116-Clone2) manifested a significantly increased survival whereas a third clone (HCT116-CloneK) manifested a significantly decreased survival relative to the parental cell line. This suggested that they were, respectively, a radioresistant and a radiosensitive clone. All three clones (clones 2, 10, K) retained their tumorigenic phenotype and formed tumors in nude mice. G-banding studies demonstrated that they were of human origin and were derived from the same parental cell line. The metaphases of HCT116-Clone2 demonstrated features commonly associated with genomic instability (i.e. mitotic catastrophe including chromosome and chromatid breaks, dicentrics and additional nonclonal markers). Data obtained by quantitative fluorescence in situ hybridization (Q- FISH) analysis failed to demonstrate any apparent correlation between the radiosensitivity and the relative telomere content of these three clones. Interestingly, HCT116-CloneK was the most resistant to several chemotherapeutic drugs (topotecan, camptothecin, etoposide and cisplatin) with diverse mechanisms of action. Also, there were no significant differences in the survivals of the three clones after treatment with UV radiation. Because of the lack of overlap among the relative sensitivities of these clones to X radiation, chemotherapeutic drugs and UV radiation, these clones may be useful models for evaluating the genetic basis of the response of human tumor cells to these treatment agents both in vitro and in vivo.

Antineoplastic Agents↗
PubMed2003

An exponential dispersion model for the distribution of human single nucleotide polymorphisms.

An analysis of 1.42 million human single nucleotide polymorphisms (SNPs), mapped by the International SNP Map Working Group, revealed an apparent power function relationship between the estimated variance and mean number of SNPs per sample bin. This relationship could be explained by the assumption that a scale invariant Poisson gamma (PG) exponential dispersion model could describe the distribution of SNPs within the bins. In this model the sample bins would contain random (Poisson distributed) numbers of identical by descent genomic segments, each with independently distributed and gamma distributed numbers of SNPs. This model was both qualitatively and quantitatively consistent with the conventional coalescent model. It agreed with the empirical cumulative distribution functions derived from the SNP maps as well as with simulated data. The model was used to estimate the heterozygosity pi, and the mean number and size of haplotype blocks for each chromosome. These estimates were consistent with measurements from conventional studies. This PG model thus provides an alternative to Monte Carlo simulation for description of the distribution of SNPs.

Computer Simulation↗
PubMed2002

Multimodality management of locally recurrent colorectal cancer.

The combined management of locally recurrent colorectal cancer shows considerable promise, but the best way to incorporate the different treatment modalities and the potential benefits remain uncertain. The case series mentioned here were derived from highly selected groups from a much larger population of patients with recurrent disease; thus fully combined management may be only appropriate for a minority of people with recurrent disease. There is a need for multicenter randomized trials to better delineate the real benefits from the combined approach. Multimodality management of recurrent colorectal cancer, however, involves more than the combination of surgery, radiation therapy, and chemotherapy for a select minority of resectable patients. It involves the use of each modality to its greatest advantage for all patients, as determined by a multidisciplinary team of specialists. We should also not confine our attention to the treatment aspects of recurrent disease alone, as the greatest promise for improved survival could be with a more general application of total mesorectal excision. Because most people who develop local recurrence of colorectal cancer will die from their disease, the main contribution of a multimodality approach may be towards palliation.

Chemotherapy, Adjuvant↗