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Biomedical subjects

Mark P Little

Publications and source records attributed to Mark P Little.

At least 19 recordsLinked to original sources
PubMed2006

Radiation-induced leukemia at doses relevant to radiation therapy: modeling mechanisms and estimating risks.

BACKGROUND: Because many cancer patients are diagnosed earlier and live longer than in the past, second cancers induced by radiation therapy have become a clinically significant issue. An earlier biologically based model that was designed to estimate risks of high-dose radiation-induced solid cancers included initiation of stem cells to a premalignant state, inactivation of stem cells at high radiation doses, and proliferation of stem cells during cellular repopulation after inactivation. This earlier model predicted the risks of solid tumors induced by radiation therapy but overestimated the corresponding leukemia risks. METHODS: To extend the model to radiation-induced leukemias, we analyzed--in addition to cellular initiation, inactivation, and proliferation--a repopulation mechanism specific to the hematopoietic system: long-range migration through the blood stream of hematopoietic stem cells (HSCs) from distant locations. Parameters for the model were derived from HSC biologic data in the literature and from leukemia risks among atomic bomb survivors who were subjected to much lower radiation doses. RESULTS: Proliferating HSCs that migrate from sites distant from the high-dose region include few preleukemic HSCs, thus decreasing the high-dose leukemia risk. The extended model for leukemia provides risk estimates that are consistent with epidemiologic data for leukemia risk associated with radiation therapy over a wide dose range. For example, when applied to an earlier case-control study of 110,000 women undergoing radiotherapy for uterine cancer, the model predicted an excess relative risk (ERR) of 1.9 for leukemia among women who received a large inhomogeneous fractionated external beam dose to the bone marrow (mean = 14.9 Gy), consistent with the measured ERR (2.0, 95% confidence interval [CI] = 0.2 to 6.4; from 3.6 cases expected and 11 cases observed). As a corresponding example for brachytherapy, the predicted ERR of 0.80 among women who received an inhomogeneous low-dose-rate dose to the bone marrow (mean = 2.5 Gy) was consistent with the measured ERR (0.62, 95% CI = -0.2 to 1.9). CONCLUSIONS: An extended, biologically based model for leukemia that includes HSC initiation, inactivation, proliferation, and, uniquely for leukemia, long-range HSC migration predicts, with reasonable accuracy, risks for radiation-induced leukemia associated with exposure to therapeutic doses of radiation.

Adult↗
PubMed2006

Early growth and adult respiratory function in men and women followed from the fetal period to adulthood.

BACKGROUND: While some studies suggest that poor fetal growth rate, as indicated by lower birth weight, is associated with poor respiratory function in childhood, findings among adults remain inconsistent. A study was undertaken to determine the association between early growth and adult respiratory function. METHODS: A longitudinal birth cohort study was performed of 5390 men and women born full term and prospectively followed from the fetal period to adulthood. Weight at birth and infancy were recorded, and forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC) were assessed by standard spirometry at age 31 years. RESULTS: Adult FEV(1) and FVC increased linearly with higher birth weight in both men and women with no apparent threshold. After adjustment for sex, adult height and other potential confounders operating through the life course, every 500 g higher birth weight was associated with a higher FEV(1) of 53.1 ml (95% CI 38.4 to 67.7) and higher FVC of 52.5 ml (95% CI 35.5 to 69.4). These positive associations persisted across categories of smoking, physical activity and body mass index, with the lowest respiratory function noted among those with lower birth weight who were smokers, led a sedentary lifestyle or were overweight. Weight gain in infancy was also positively associated with adult lung function. CONCLUSION: Birth weight is continuously and independently associated with adult respiratory function. It is plausible that poor growth in early life may restrict normal lung growth and development, which could have long-term consequences on lung function later in life.

Adult↗
PubMed2006

A multi-compartment cell repopulation model allowing for inter-compartmental migration following radiation exposure, applied to leukaemia.

There is much uncertainty about cancer risks at the high radiation doses used in radiotherapy (RT). It has generally been assumed that cancer induction decreases rapidly at high doses due to cell killing. However, this is not seen in all RT groups, and a model recently developed by Sachs and Brenner [2005. Solid tumor risks after high doses of ionizing radiation. Proc. Natl Acad. Sci. USA 102, 13040-13045] proposed a mechanism for repopulation of cells after radiation exposure that explained why this might happen, at least for solid tumours. In this paper, this model is generalized to allow for heterogeneity in the dose received, and various alternate patterns of repopulation are also considered. The model is fitted to the Japanese atomic bomb survivor leukaemia incidence data, and data for various therapeutically irradiated groups. Two sets of parameters from these model fits are used to assess the sensitivity of model predictions. It is shown that in general allowing for heterogeneity in dose distribution and haematopoietic stem cell migration results in lower risks than the same average dose administered uniformly and without such migration, although this does not hold in the limiting case of complete stem cell repopulation between radiation dose fractions. We also investigate the difference made by assuming a compartmental repopulation signal, and a global repopulation signal. In general we show that in the absence of stochastic extinction, compartmental repopulation always predicts a larger number of mutated cells than global repopulation. However, in certain dose regimes stochastic extinction cannot be ignored, and in these cases the numbers of mutated cells predicted with global repopulation can exceed that for compartmental repopulation. In general, mutant cell numbers are highly overdispersed, with variance much greater than the mean.

Cell Count↗
PubMed2006

Stochastic modelling of colon cancer: is there a role for genomic instability?

Three stochastic models of genomic instability recently developed by Little and Wright (Math. Biosci., (2003) 183, 111-34), with two, three and five stages, and the two-stage genomic instability model of Nowak et al. (Proc. Natl Acad. Sci. USA, (2002) 99, 16226-16231) are compared with the four-stage model proposed by Luebeck and Moolgavkar (Proc. Natl Acad. Sci. USA, (2002) 99, 15095-15100) that does not assume such an instability mechanism. All models are fitted to US colon cancer incidence data. The best fitting models are the two-stage model of Nowak et al. and the two-stage model of Little and Wright, with the four-stage model of Luebeck and Moolgavkar not markedly inferior. The fits of the three-stage and five-stage models are somewhat worse (P<0.05), the five-stage model fitting particularly poorly (P<0.01). Both optimal genomic instability models predict cellular mutation rates that are at least 10 000 times higher after genomic destabilization, for both sexes. Therefore, the results of this paper are somewhat at variance with those of previous analyses of Little and Wright in suggesting that equivalently good fit may be obtained by models that do not assume a role for genomic destabilization in the induction of colon cancer as for those that do.

Colonic Neoplasms↗
PubMed2005

Human infection patterns and heterogeneous exposure in river blindness.

Here we analyze patterns of human infection with Onchocerca volvulus (the cause of river blindness) in different continents and ecologies. In contrast with some geohelminths and schistosome parasites whose worm burdens typically exhibit a humped pattern with host age, patterns of O. volvulus infection vary markedly with locality. To test the hypothesis that such differences are partly due to heterogeneity in exposure to vector bites, we develop an age- and sex-structured model for intensity of infection, with parasite regulation within humans and vectors. The model is fitted to microfilarial data from savannah villages of northern Cameroon, coffee fincas of central Guatemala, and forest-dwelling communities of southern Venezuela that were recorded before introducing ivermectin treatment. Estimates of transmission and infection loads are compared with entomological and epidemiological field data. Host age- and sex-heterogeneous exposure largely explains locale-specific infection patterns in onchocerciasis (whereas acquired protective immunity has been invoked for other helminth infections). The basic reproductive number, R0, ranges from 5 to 8, which is slightly above estimates for other helminth parasites but well below previously presented values.

Age Factors↗
PubMed2005

Hemoglobin concentration in pregnancy and perinatal mortality: a London-based cohort study.

OBJECTIVE: Failure of fetal growth during pregnancy, and preterm birth, are the major causes of stillbirth and early neonatal death. The objective of the study was to determine the association between maternal hemoglobin concentration during pregnancy and perinatal mortality. STUDY DESIGN: The design was prospective, using data on 222,614 first singleton pregnancies in the St Mary's Maternity Information System database in the Northwest Thames region of London. RESULTS: The association of perinatal mortality with maternal hemoglobin at first antenatal check was not statistically significant (P>.10), but a statistically significant (P<.001) U-shaped pattern was found with lowest recorded maternal hemoglobin concentration. Both early neonatal mortality and stillbirth rates were statistically significantly (P<.005) associated with lowest maternal hemoglobin concentration. The relationship of lowest hemoglobin with early neonatal mortality was largely mediated by the effect of preterm birth, and that between lowest hemoglobin and stillbirth by fetal growth restriction. The lowest perinatal mortality was associated with a lowest recorded maternal hemoglobin concentration of between 9-11 g/dL. CONCLUSION: There is an optimal range of lowest hemoglobin concentration in pregnancy, and on either side of this perinatal mortality is increased. The effect of lowest hemoglobin is largely mediated through associations with preterm birth and fetal growth restriction.

Birth Weight↗
PubMed2004

Flexible dose-response models for Japanese atomic bomb survivor data: Bayesian estimation and prediction of cancer risk.

Generalised absolute risk models were fitted to the latest Japanese atomic bomb survivor cancer incidence data using Bayesian Markov Chain Monte Carlo methods, taking account of random errors in the DS86 dose estimates. The resulting uncertainty distributions in the relative risk model parameters were used to derive uncertainties in population cancer risks for a current UK population. Because of evidence for irregularities in the low-dose dose response, flexible dose-response models were used, consisting of a linear-quadratic-exponential model, used to model the high-dose part of the dose response, together with piecewise-linear adjustments for the two lowest dose groups. Following an assumed administered dose of 0.001 Sv, lifetime leukaemia radiation-induced incidence risks were estimated to be 1.11 x 10(-2) Sv(-1) (95% Bayesian CI -0.61, 2.38) using this model. Following an assumed administered dose of 0.001 Sv, lifetime solid cancer radiation-induced incidence risks were calculated to be 7.28 x 10(-2) Sv(-1) (95% Bayesian CI -10.63, 22.10) using this model. Overall, cancer incidence risks predicted by Bayesian Markov Chain Monte Carlo methods are similar to those derived by classical likelihood-based methods and which form the basis of established estimates of radiation-induced cancer risk.

Algorithms↗
PubMed2004

Maternal blood pressure in pregnancy, birth weight, and perinatal mortality in first births: prospective study.

OBJECTIVE: To investigate the relation of diastolic blood pressure in pregnancy with birth weight and perinatal mortality. DESIGN: Prospective study. SETTING: 15 maternity units in one London health region, 1988-2000. PARTICIPANTS: 210 814 first singleton births of babies weighing more than 200 g among mothers with no hypertension before 20 weeks' gestation and without proteinuria, delivering between 24 and 43 weeks' gestation. MAIN OUTCOME MEASURES: Birth weight and perinatal mortality. RESULTS: The mean (SD) birth weight of babies born to mothers with no hypertension before 20 weeks' gestation or proteinuria was 3282 g (545 g) and there were 1335 perinatal deaths, compared with 94 perinatal deaths among women with proteinuria or a history of hypertension. Diastolic blood pressure at booking for antenatal checks was progressively higher from weeks 34 to 40 of gestation. The birth weight of babies being delivered after 34 weeks was highest for highest recorded maternal diastolic blood pressures of between 70 and 80 mm Hg and lower for blood pressures outside this range. Both low and high diastolic blood pressures were associated with statistically significantly higher perinatal mortality. Using a linear quadratic model, 94 of 825 (11.4%) perinatal deaths could be attributed to mothers having blood pressure differing from the optimal blood pressure (82.7 mm Hg) predicted by the fitted model. Most of these excess deaths occurred with blood pressures below the optimal value. CONCLUSIONS: Both low and high diastolic blood pressures in women during pregnancy are associated with small babies and high perinatal mortality.

Adolescent↗
PubMed2004

Threshold and other departures from linear-quadratic curvature in the non-cancer mortality dose-response curve in the Japanese atomic bomb survivors.

Recently released data on non-cancer mortality in Japanese atomic bomb survivors are analysed using a variety of generalised relative risk models that take account of errors in estimates of dose to assess the dose-response at low doses. If linear-threshold, quadratic-threshold or linear-quadratic-threshold relative risk models (the dose-response is assumed to be linear, quadratic or linear-quadratic above the threshold, respectively) are fitted to the non-cancer data there are no statistically significant ( p>0.10) indications of threshold departures from linearity, quadratic curvature or linear-quadratic curvature. These findings are true irrespective of the assumed magnitude of dosimetric error, between 25%-45% geometric standard deviations. In general, increasing the assumed magnitude of dosimetric error had little effect on the central estimates of the threshold, but somewhat widened the associated confidence intervals. If a power of dose model is fitted, there is little evidence ( p>0.10) that the power of dose in the dose-response is statistically significantly different from 1, again irrespective of the assumed magnitude of dosimetric errors in the range 25%-45%. Again, increasing the size of the errors resulted in wider confidence intervals on the power of dose, without marked effect on the central estimates. In general these findings remain true for various non-cancer disease subtypes.

Animals↗
PubMed2004

Incidence of blindness during the Onchocerciasis control programme in western Africa, 1971-2002.

BACKGROUND: Infection with Onchocerca volvulus is associated with the prevalence of severe visual impairment and blindness. However, longitudinal studies of the incidence of blindness caused by onchocerciasis are scarce. METHODS: The relationship, at the individual level, between infection with O. volvulus microfilariae and bilateral blindness was examined, by use of data collected, during the Onchocerciasis Control Programme in western Africa (OCP), from 2315 villages in 11 countries. The data were analyzed by Poisson maximum-likelihood techniques with adjustment for overdispersion. RESULTS: A total of 297,756 persons were eligible for follow-up in the cohort, and, during 1971-2001, these persons accumulated 367,788 person-years of follow-up without blindness. A total of 673 bilateral cases of blindness occurred during this period; 29.7% were caused by onchocerciasis. After ivermectin therapy was introduced (during 1988-2001), only 19.6% of cases were caused by onchocerciasis. The incidence of blindness was significantly and positively associated with increasing microfilarial burden (P<.001). Overall, female subjects had an ~40% lower risk of becoming blind than did male subjects (P<.001). After an initially high incidence of blindness at the beginning of the OCP, the rate of blindness from causes other than onchocerciasis remained approximately constant during follow-up. CONCLUSIONS: We demonstrate, in a comprehensive data set and in both sexes, a direct relationship between microfilarial load and the incidence of blindness.

Adolescent↗
PubMed2004

Does gestation vary by ethnic group? A London-based study of over 122,000 pregnancies with spontaneous onset of labour.

BACKGROUND: Evidence exists that normal gestational length varies with ethnicity. This UK-based study compares gestational length amongst a cohort of white European, Black and Asian women. METHODS: The cohort comprised 122 415 nulliparous women with singleton live fetuses at the time of spontaneous labour, giving birth in the former North West Thames Health Region, London, UK. RESULTS: The median gestational age at delivery was 39 weeks in Blacks and Asians and 40 weeks in white Europeans. Black women with normal body mass index (BMI) (18.5-24.9 kg/m(2)) had increased odds of preterm delivery (odds ratio [OR] = 1.33, 95% CI: 1.15, 1.56, adjusted for deprivation and BMI) compared with white Europeans. The OR of preterm delivery was also increased in Asians compared with white Europeans (OR = 1.45, 95% CI: 1.33, 1.56, adjusted for single unsupported status and smoking). Meconium stained amniotic fluid, which is a sign of fetal maturity, was statistically significantly more frequent in preterm Black and Asian infants and term Black infants compared with white European infants. CONCLUSIONS: This research suggests that normal gestational length is shorter in Black and Asian women compared with white European women and that fetal maturation may occur earlier.

Adolescent↗
PubMed2002

Modelling lung tumour risk in radon-exposed uranium miners using generalizations of the two-mutation model of Moolgavkar, Venzon and Knudson.

PURPOSES: To model radon-induced lung cancer in uranium miners using a quasi-biological model of carcinogenesis. MATERIALS AND METHODS: Fitting of generalizations of the stochastic two-mutation carcinogenesis model of Moolgavkar, Venzon and Knudson to a case-control dataset nested within the cohort and to the full cohort of lung cancer mortality in the Colorado Plateau uranium miners, taking account of exposure to cigarette smoke and to radon daughters. RESULTS: Models with three mutations gave adequate descriptions of the time and age patterns of radon-daughter-induced excess lung tumour mortality. The overall fit of the two-mutation model to the case-control data was somewhat worse than that of the three-mutation model. For both the optimal two- and three-mutation models radon daughters and cigarette smoke were assumed to act on the first mutation rate. In the optimal two-mutation model, radon daughters also modified the intermediate cell death or differentiation rate. In the optimal three-mutation model, radon daughters modified the second mutation rate. In all models, the action of radon daughters and cigarette smoke was markedly non-linear, particularly in their action on the mutation rates. The optimal two- and three-mutation models fitted to the cohort data were of slightly different form to those fitted to the case-control data. The model fits to the cohort data are preferred to those to the case-control data on grounds of plausibility. CONCLUSIONS: Quasi-biological carcinogenesis models with three mutations give adequate descriptions of the time and age patterns of radon-daughter-induced excess lung tumour mortality. The overall fit of the two-mutation model is somewhat worse than that of the three-mutation model.

Humans↗
PubMed2002

Absence of evidence for differences in the dose-response for cancer and non-cancer endpoints by acute injury status in the Japanese atomic-bomb survivors.

PURPOSES: To ascertain possible evidence for radiosensitive subgroups in the Japanese atomic-bomb survivors. MATERIALS AND METHODS: Time- and age-adjusted relative risk models were fitted to the Japanese atomic-bomb survivor mortality data, taking account of the modifying effects of acute injury status and adjusting for random dosimetric errors. RESULTS: For leukaemia, there were statistically significantly higher relative risks among those persons reporting either epilation (two-sided p=0.03) or burns (two-sided p=0.02), but after adjustment is made for the effects of dosimetric error these results become statistically non-significant (two-sided p>0.05) For all other endpoints (cancers other than leukaemia, benign neoplasms, cardiovascular disease, non-cancer and non-cardiovascular disease) there were no statistically significant modifying effects on relative risk of acute injury status, whether or not adjustment is made for the effects of dosimetric error. CONCLUSIONS: Apart from leukaemia, there are generally no indications for cancer or other disease endpoints of variations in dose-response by acute injury status. The increased risks observed for leukaemia among those reporting epilation or burns are much diminished after adjustment for dosimetric error, and so there is no strong evidence of a sensitive subgroup within the Life Span Study cohort.

Acute Disease↗