Modeling the survival of T-cell lymphocytes using compound branching processes

Radiotherapy has been a method of choice in cancer treatment for a number of years. Mathematical modeling is an important tool in studying the survival behavior of any cell as well as its radiosensitivity. One particular cell under investigation is the normal T-cell, the radiosensitivity of which may be indicative to the patient's tolerance to radiation doses.^ The model derived is a compound branching process with a random initial population of T-cells that is assumed to have compound distribution. T-cells in any generation are assumed to double or die at random lengths of time. This population is assumed to undergo a random number of generations within a period of time. The model is then used to obtain an estimate for the survival probability of T-cells for the data under investigation. This estimate is derived iteratively by applying the likelihood principle. Further assessment of the validity of the model is performed by simulating a number of subjects under this model.^ This study shows that there is a great deal of variation in T-cells survival from one individual to another. These variations can be observed under normal conditions as well as under radiotherapy. The findings are in agreement with a recent study and show that genetic diversity plays a role in determining the survival of T-cells. ^

Maximal exercise hemodynamics and risk of mortality in apparently healthy men and women

The use of exercise electrocardiography (ECG) to detect latent coronary heart disease (CHD) is discouraged in apparently healthy populations because of low sensitivity. These recommendations however, are based on the efficacy of evaluation of ischemia (ST segment changes) with little regard for other measures of cardiac function that are available during exertion. The purpose of this investigation was to determine the association of maximal exercise hemodynamic responses with risk of mortality due to all-causes, cardiovascular disease (CVD), and coronary heart disease (CHD) in apparently healthy individuals. Study participants were 20,387 men (mean age = 42.2 years) and 6,234 women (mean age = 41.9 years) patients of a preventive medicine center in Dallas, TX examined between 1971 and 1989. During an average of 8.1 years of follow-up, there were 348 deaths in men and 66 deaths in women. In men, age-adjusted all-cause death rates (per 10,000 person years) across quartiles of maximal systolic blood pressure (SBP) (low to high) were: 18.2, 16.2, 23.8, and 24.6 (p for trend $<$0.001). Corresponding rates for maximal heart rate were: 28.9, 15.9, 18.4, and 15.1 (p trend $<$0.001). After adjustment for confounding variables including age, resting systolic pressure, serum cholesterol and glucose, body mass index, smoking status, physical fitness and family history of CVD, risks (and 95% confidence interval (CI)) of all-cause mortality for quartiles of maximal SBP, relative to the lowest quartile, were: 0.96 (0.70-1.33), 1.36 (1.01-1.85), and 1.37 (0.98-1.92) for quartiles 2-4 respectively. Similar risks for maximal heart rate were: 0.61 (0.44-0.85), 0.69 (0.51-0.93), and 0.60 (0.41-0.87). No associations were noted between maximal exercise rate-pressure product mortality. Similar results were seen for risk of CVD and CHD death. In women, similar trends in age-adjusted all-cause and CVD death rates across maximal SBP and heart rate categories were observed. Sensitivity of the exercise test in predicting mortality was enhanced when ECG results were evaluated together with maximal exercise SBP or heart rate with a concomitant decrease in specificity. Positive predictive values were not improved. The efficacy of the exercise test in predicting mortality in apparently healthy men and women was not enhanced by using maximal exercise hemodynamic responses. These results suggest that an exaggerated systolic blood pressure or an attenuated heart rate response to maximal exercise are risk factors for mortality in apparently healthy individuals. ^

Genetic epidemiologic methods in risk determination in Li-Fraumeni syndrome

Li-Fraumeni syndrome (LFS) is characterized by a variety of neoplasms occurring at a young age with an apparent autosomal dominant transmission. Individuals in pedigrees with LFS have high incidence of second malignancies. Recently LFS has been found to be associated with germline mutations of a tumor-suppressor gene, p53. Because LFS is rare and indeed not a clear-cut disease, it is not known whether all cases of LFS are attributable to p53 germline mutations and how p53 plays in cancer occurrence in such cancer syndrome families. In the present study, DNAs from constitutive cells of two-hundred and thirty-three family members from ten extended pedigrees were screened for p53 mutations. Six out of the ten LFS families had germline mutations at the p53 locus, including point and deletion mutations. In these six families, 55 out of 146 members were carriers of p53 mutations. Except one, all mutations occurred in exons 5 to 8 (i.e., the "hot spot" region) of the p53 gene. The age-specific penetrance of cancer was estimated after the genotype for each family member at risk was determined. The penetrance was 0.15, 0.29, 0.35, 0.77, and 0.91 by 20, 30, 40, 50 and 60 year-old, respectively, in male carriers; 0.19, 0.44, 0.76, and 0.90 by 20, 30, 40, and 50 year-old, respectively, in female carriers. These results indicated that one cannot escape from tumorigenesis if one inherits a p53 mutant allele; at least ninety percent of p53 carriers will develop cancer by the age of 60. To evaluate the possible bias due to the unexamined blood-relatives in LFS families, I performed a simulation analysis in which a p53 genotype was assigned to each unexamined person based on his cancer status and liability to cancer. The results showed that the penetrance estimates were not biased by the unexamined relatives. I also determined the sex, site, and age-specific penetrance of breast cancer in female carriers and lung cancer in male carriers. The penetrance of breast cancer in female carriers was 0.81 by age 45; the penetrance of lung cancer in male carriers was 0.78 by age 60, indicating that p53 play a key role for tumorigenesis in common cancers. ^

Epidemiology of allergic gastroenteritis in socio-culture perspective of rural Egypt

Diarrhea is a major public health problem in developing countries among infants and young children. Not all episodes of diarrhea are confirmed as infectious, suggesting alternate mechanisms. One such is immunoglobulin E (IgE) mediated or allergic diarrhea that can be seen in food allergy. In order to determine the relation between allergic gastroenteritis and feeding practice, a cohort of 152 infants were followed from birth to one year age in a rural community of Egypt between October, 1987 to April, 1988 were analyzed. In multivariate analysis of the data, statistically conclusive higher risk had been observed with presence of factors, like consumption of milk pudding (RR = 7.4, CI = 1.5-36.2 and p = 0.01), infant's age 3-6 months (RR = 7.7, CI = 1.3-45.9 and p = 0.02), infants whose mothers were vaccinated antenatally (RR = 3.1, CI = 1.3-7.0 and p = 1.3-7.0, p = 0.0) and wet-nursed infants (RR = 2.7, CI = 1.1-6.5 and p = 0.02). In contrast, infants who were completely breast-fed (RR = 0.13, CI = 0.02-0.6 and p = 0.01), and infants family owning a television set (RR = 0.29, CI = 0.1-0.6 and p = 0.0) were less likely to develop allergic gastroenteritis. The role of IgE on development of persistent diarrhea was also examined in a nested case-control design. Multivariate analysis revealed a significant association between detection of fecal IgE and development of persistent diarrhea compared to acute diarrhea (OR = 3.32, CI = 1.0-10.9 and p = 0.04) and health or non diarrhea (OR = 4.8, CI = 1.07-21.7 and p = 0.03) controls. ^

Natural history of placebo treatment in adults acquiring travelers' diarrhea in Mexico

The natural history of placebo treated travelers' diarrhea and the prognostic factors of recovery from diarrhea were evaluated using 9 groups of placebo treated subjects from 9 clinical trial studies conducted since 1975, for use as a historical control in the future clinical trial of antidiarrheal agents. All of these studies were done by the same group of investigators in one site (Guadalajara, Mexico). The studies are similar in terms of population, measured parameters, microbiologic identification of enteropathogens and definitions of parameters. The studies had two different durations of followup. In some studies, subjects were followed for two days, and in some they were followed for five days.^ Using definitions established by the Infectious Diseases society of America and the Food and Drug Administration, the following efficacy parameters were evaluated: Time to last unformed stool (TLUS), number of unformed stools post-initiation of placebo treatment for five consecutive days of followup, microbiologic cure, and improvement of diarrhea. Among the groups that were followed for five days, the mean TLUS ranged from 59.1 to 83.5 hours. Fifty percent to 78% had diarrhea lasting more than 48 hours and 25% had diarrhea more than five days. The mean number of unformed stools passed on the first day post-initiation of therapy ranged from 3.6 to 5.8 and, for the fifth day ranged from 0.5 to 1.5. By the end of followup, diarrhea improved in 82.6% to 90% of the subjects. Subjects with enterotoxigenic E. coli had 21.6% to 90.0% microbiologic cure; and subjects with shigella species experienced 14.3% to 60.0% microbiologic cure.^ In evaluating the prognostic factors of recovery from diarrhea (primary efficacy parameter in evaluating the efficacy of antidiarrheal agents against travelers' diarrhea). The subjects from five studies were pooled and the Cox proportional hazard model was used to evaluate the predictors of prolonged diarrhea. After adjusting for design characteristics of each trial, fever with a rate ratio (RR) of 0.40, presence of invasive pathogens with a RR of 0.41, presence of severe abdominal pain and cramps with a RR of 0.50, number of watery stools more than five with a RR of 0.60, and presence of non-invasive pathogens with a RR of 0.84 predicted a longer duration of diarrhea. Severe vomiting with a RR of 2.53 predicted a shorter duration of diarrhea. The number of soft stools, presence of fecal leukocytes, presence of nausea, and duration of diarrhea before enrollment were not associated with duration of diarrhea. ^

RELATION OF TYPE OF REPORTED ILLNESSES TO PATTERN OF USE OF THE STUDENT HEALTH CENTER BY THE INTERNATIONAL STUDENTS AT TEXAS SOUTHERN UNIVERSITY, HOUSTON, TEXAS

The state of knowledge on the relation of stress factors, health problems and health service utilization among university students is limited. Special problems of stress exist for the international students due to their having to adjust to a new environment. It is this latter problem area that provides the focus for this study. Recognizing there are special stress factors affecting the international students, it is first necessary to see if the problems of cultural adaptation affect them to any greater degree than American students attending the same university.^ To make the comparison, the study identified a number of health problems of both American and international students and related their frequency to the use of the Student Health Center. The expectation was that there would be an association between the number of health problems and the number of life change events experienced by these students and between the number of health problems and stresses from social factors. It was also expected that the number of health problems would decline with the amount of social support.^ The population chosen were students newly enrolled in Texas Southern University, Houston, Texas in the Fall Semester of 1979. Two groups were selected at random: 126 international and 126 American students. The survey instrument was a self-administered questionnaire. The response rate was 90% (114) for the international and 94% (118) for the American students.^ Data analyses consisted of both descriptive and inferential statistics. Chi-squares and correlation coefficients were the statistics used in comparing the international students and the American students.^ There was a weak association between the number of health problems and the number of life change events, as reported by both the international and the American students. The study failed to show any statistically significant association between the number of stress from social factors and the number of health problems. It also failed to show an association between the number of health problems and the amount of social support. These findings applied to both the international and the American students.^ One unexpected finding was that certain health problems were reported by more American than international students. There were: cough, diarrhea, and trouble in sleeping. Another finding was that those students with health insurance had a higher level of utilization of the Health Center than those without health insurance. More international than American students utilized the Student Health Center.^ In comparing the women students, there was no statistical significant difference in their reported fertility related health problems.^ The investigator recommends that in follow-up studies, instead of grouping all international students together, that they be divided by major nationalities represented in the student body; that is, Iranians, Nigerians and others. ^

FACTORS INFLUENCING CHOICE OF CONTRACEPTIVE METHOD AMONG MARRIED FECUND WOMEN WHO INTEND NO ADDITIONAL BIRTHS: HEALTH BELIEF MODEL AND ECONOMIC PERSPECTIVES

This research examined to what extent Health Belief Model (HBM) and socioeconomic variables were useful in explaining the choice whether or not more effective contraceptive methods were used among married fecund women intending no additional births. The source of the data was the 1976 National Survey of Family Growth conducted under the auspices of the National Center for Health Statistics. Using the HBM as a framework for multivariate analyses limited support was found (using available measures) that the HBM components of motivation and perceived efficacy influence the likelihood of more effective contraceptive method use. Support was also found that modifying variables suggested by the HBM can influence the effects of HBM components on the likelihood of more effective method use. Socioeconomic variables were found, using all cases and some subgroups, to have a significant additional influence on the likelihood of use of more effective methods. Limited support was found for the concept that the greater the opportunity costs of an unwanted birth the greater the likelihood of use of more effective contraceptive methods. This research supports the use of HBM and socioeconomic variables to explain the likelihood of a protective health behavior, use of more effective contraception if no additional births are intended.^

Survey analysis on dental infection control & occupational safety from India---1999 & 2010

The objective was to study knowledge, attitudes, practice (KAP) and needs regarding infection control measures using two cross-sectional surveys from 1999 and 2010 conducted in India. Both data collection instruments had only about 35 comparable variables in common. In 1999, there were 456 respondents (dentists) who completed a self-administered survey instrument compared to 272 respondents in 2010. Both the 1999 and 2010 samples were mutually independent with no overlap, had regional differences, and therefore, were not completely comparable for changes in KAP over time. While almost all respondents from both surveys felt that education in dental safety was needed and wanted mandatory dental safety curriculum in dental schools, severe inadequacies in dental safety knowledge, protection against immunizable diseases, and practice of universal precaution were noted. Data from the study demonstrated that there is a substantial opportunity to improve the knowledge, attitude and practice of dental infection control and occupational safety in India. Few respondents (27%) reported that the infectious disease status of a patient is always known and a significant number reported that they had the right to refuse care for patients of known infectious disease status. This indicates that Stigma in treating HIV/AIDS patients remains a concern, which in turn suggests that a stronger focus on educating dentists about dental safety and on stigma and infectious disease is needed. Information obtained from this study could be utilized for developing policies oriented towards increasing dental safety educational efforts, in both dental schools as curriculum, and for practicing dentists through professional updates or continuing dental education.^

The application of principal component analysis on human development indicators: Temporal approach from 1999 to 2010

Background and Objective. Ever since the human development index was published in 1990 by the United Nations Development Programme (UNDP), many researchers started searching and corporative studying for more effective methods to measure the human development. Published in 1999, Lai’s “Temporal analysis of human development indicators: principal component approach” provided a valuable statistical way on human developmental analysis. This study presented in the thesis is the extension of Lai’s 1999 research. ^ Methods. I used the weighted principal component method on the human development indicators to measure and analyze the progress of human development in about 180 countries around the world from the year 1999 to 2010. The association of the main principal component obtained from the study and the human development index reported by the UNDP was estimated by the Spearman’s rank correlation coefficient. The main principal component was then further applied to quantify the temporal changes of the human development of selected countries by the proposed Z-test. ^ Results. The weighted means of all three human development indicators, health, knowledge, and standard of living, were increased from 1999 to 2010. The weighted standard deviation for GDP per capita was also increased across years indicated the rising inequality of standard of living among countries. The ranking of low development countries by the main principal component (MPC) is very similar to that by the human development index (HDI). Considerable discrepancy between MPC and HDI ranking was found among high development countries with high GDP per capita shifted to higher ranks. The Spearman’s rank correlation coefficient between the main principal component and the human development index were all around 0.99. All the above results were very close to outcomes in Lai’s 1999 report. The Z test result on temporal analysis of main principal components from 1999 to 2010 on Qatar was statistically significant, but not on other selected countries, such as Brazil, Russia, India, China, and U.S.A.^ Conclusion. To synthesize the multi-dimensional measurement of human development into a single index, the weighted principal component method provides a good model by using the statistical tool on a comprehensive ranking and measurement. Since the weighted main principle component index is more objective because of using population of nations as weight, more effective when the analysis is across time and space, and more flexible when the countries reported to the system has been changed year after year. Thus, in conclusion, the index generated by using weighted main principle component has some advantage over the human development index created in UNDP reports.^

Risk factors of pneumonia in traumatic spinal-cord-injured patients

Pneumonia is a well-documented and common respiratory infection in patients with acute traumatic spinal cord injuries, and may recur during the course of acute care. Using data from the North American Clinical Trials Network (NACTN) for Spinal Cord Injury, the incidence, timing, and recurrence of pneumonia were analyzed. The two main objectives were (1) to investigate the time and potential risk factors for the first occurrence of pneumonia using the Cox Proportional Hazards model, and (2) to investigate pneumonia recurrence and its risk factors using a Counting Process model that is a generalization of the Cox Proportional Hazards model. The results from survival analysis suggested that surgery, intubation, American Spinal Injury Association (ASIA) grade, direct admission to a NACTN site and age (older than 65 or not) were significant risks for first event of pneumonia and multiple events of pneumonia. The significance of this research is that it has the potential to identify patients at the time of admission who are at high risk for the incidence and recurrence of pneumonia. Knowledge and the time of occurrence of pneumonias are important factors for the development of prevention strategies and may also provide some insights into the selection of emerging therapies that compromise the immune system. ^

Identification of micro-RNAs targeting genes of PI3K/AKT pathway in ovarian cancer

Ovarian cancer is the leading cause of cancer-related death for females due to lack of specific early detection method. It is of great interest to find molecular-based biomarkers which are sensitive and specific to ovarian cancer for early diagnosis, prognosis and therapeutics. miRNAs have been proposed to be potential biomarkers that could be used in cancer prevention and therapeutics. The current study analyzed the miRNA and mRNA expression data extracted from the Cancer Genome Atlas (TCGA) database. Using simple linear regression and multiple regression models, we found 71 miRNA-mRNA pairs which were negatively associated between 56 miRNAs and 24 genes of PI3K/AKT pathway. Among these miRNA and mRNA target pairs, 9 of them were in agreement with the predictions from the most commonly used target prediction programs including miRGen, miRDB, miRTarbase and miR2Disease. These shared miRNA-mRNA pairs were considered to be the most potential genes that were involved in ovarian cancer. Furthermore, 4 of the 9 target genes encode cell cycle or apoptosis related proteins including Cyclin D1, p21, FOXO1 and Bcl2, suggesting that their regulator miRNAs including miR-16, miR-96 and miR-21 most likely played important roles in promoting tumor growth through dysregulated cell cycle or apoptosis. miR-96 was also found to directly target IRS-1. In addition, the results showed that miR-17 and miR-9 may be involved in ovarian cancer through targeting JAK1. This study might provide evidence for using miRNA or miRNA profile as biomarker.^

Global practice experience: A useful lens for understanding patient and staff perceptions of successful integration of health information technology in primary care

Making healthcare comprehensive and more efficient remains a complex challenge. Health Information Technology (HIT) is recognized as an important component of this transformation but few studies describe HIT adoption and it's effect on the bedside experience by physicians, staff and patients. This study applied descriptive statistics and correlation analysis to data from the Patient-Centered Medical Home National Demonstration Project (NDP) of the American Academy of Family Physicians. Thirty-six clinics were followed for 26 months by clinician/staff questionnaires and patient surveys. This study characterizes those clinics as well as staff and patient perspectives on HIT usefulness, the doctor-patient relationship, electronic medical record (EMR) implementation, and computer connections in the practice throughout the study. The Global Practice Experience factor, a composite score related to key components of primary care, was then correlated to clinician and patient perspectives. This study found wide adoption of HIT among NDP practices. Patient perspectives on HIT helpfulness on the doctor-patient showed a suggestive trend that approached statistical significance (p = 0.172). Clinicians and staff noted successful integration of EMR into clinic workflow and their perception of helpfulness to the doctor-patient relationship show a suggestive increase also approaching statistical significance (p=0.06). GPE was correlated with clinician/staff assessment of a helpful doctor-patient relationship midway through the study (R 0.460, p = 0.021) with the remaining time points nearing statistical significance. GPE was also correlated to both patient perspectives of EMR helpfulness in the doctor-patient relationship (R 0.601, p = 0.001) and computer connections (R 0.618, p = 0.0001) at the start of the study. ^

Effect of patient accrual patterns on power and size of log-rank test for time-to-event outcome in clinical trials

The determination of size as well as power of a test is a vital part of a Clinical Trial Design. This research focuses on the simulation of clinical trial data with time-to-event as the primary outcome. It investigates the impact of different recruitment patterns, and time dependent hazard structures on size and power of the log-rank test. A non-homogeneous Poisson process is used to simulate entry times according to the different accrual patterns. A Weibull distribution is employed to simulate survival times according to the different hazard structures. The current study utilizes simulation methods to evaluate the effect of different recruitment patterns on size and power estimates of the log-rank test. The size of the log-rank test is estimated by simulating survival times with identical hazard rates between the treatment and the control arm of the study resulting in a hazard ratio of one. Powers of the log-rank test at specific values of hazard ratio (≠1) are estimated by simulating survival times with different, but proportional hazard rates for the two arms of the study. Different shapes (constant, decreasing, or increasing) of the hazard function of the Weibull distribution are also considered to assess the effect of hazard structure on the size and power of the log-rank test. ^

Evaluation of CHIP perinatal program outcomes in Harris County, Texas

This study compared initial year trends in prenatal care and birth outcomes of women enrolled in the Texas Children's Health Insurance Program (CHIP) Perinatal program to trends in Medicaid program women. The study utilized claims data from Community Health Choice (CHC), a health plan in Harris County, Texas that provides coverage to both populations. Quarterly data was analyzed and compared for the first two years of the CHIP Perinatal program (2007-2008) to determine if outcome trends for the CHIP program improved over the outcome trends seen with those enrolled in Medicaid. Study findings indicate an increase in the quarterly prenatal care utilization for the CHIP Perinatal population from 2007 to 2008 and the associated birth weights of babies delivered also had marginal improvements during the same timeframe. Enrollees in Medicaid continued to have overall better outcomes than those enrolled within the CHIP Perinatal program. However, the study showed that the rate of improvement in both prenatal care utilization and birth outcomes were greater for the CHIP Perinatal enrollees than those enrolled in Medicaid. ^ The majority of these improvements were significant when comparing each coverage program and from year to year. Lastly, the study showed that there was a correlation between prenatal care utilization and birth outcomes. However, further analysis of the data could not conclusively indicate that access to prenatal care services provided by the CHIP Perinatal program contributed to the increases observed in utilization and birth outcomes for the study's sample population.^

A hybrid method in combining treatment effects from matched and unmatched studies

In the biomedical studies, the general data structures have been the matched (paired) and unmatched designs. Recently, many researchers are interested in Meta-Analysis to obtain a better understanding from several clinical data of a medical treatment. The hybrid design, which is combined two data structures, may create the fundamental question for statistical methods and the challenges for statistical inferences. The applied methods are depending on the underlying distribution. If the outcomes are normally distributed, we would use the classic paired and two independent sample T-tests on the matched and unmatched cases. If not, we can apply Wilcoxon signed rank and rank sum test on each case. ^ To assess an overall treatment effect on a hybrid design, we can apply the inverse variance weight method used in Meta-Analysis. On the nonparametric case, we can use a test statistic which is combined on two Wilcoxon test statistics. However, these two test statistics are not in same scale. We propose the Hybrid Test Statistic based on the Hodges-Lehmann estimates of the treatment effects, which are medians in the same scale.^ To compare the proposed method, we use the classic meta-analysis T-test statistic on the combined the estimates of the treatment effects from two T-test statistics. Theoretically, the efficiency of two unbiased estimators of a parameter is the ratio of their variances. With the concept of Asymptotic Relative Efficiency (ARE) developed by Pitman, we show ARE of the hybrid test statistic relative to classic meta-analysis T-test statistic using the Hodges-Lemann estimators associated with two test statistics.^ From several simulation studies, we calculate the empirical type I error rate and power of the test statistics. The proposed statistic would provide effective tool to evaluate and understand the treatment effect in various public health studies as well as clinical trials.^