An empirical evaluation of the Random Forests classifier models for variable selection in a large-scale lung cancer case-control study

Random Forests™ is reported to be one of the most accurate classification algorithms in complex data analysis. It shows excellent performance even when most predictors are noisy and the number of variables is much larger than the number of observations. In this thesis Random Forests was applied to a large-scale lung cancer case-control study. A novel way of automatically selecting prognostic factors was proposed. Also, synthetic positive control was used to validate Random Forests method. Throughout this study we showed that Random Forests can deal with large number of weak input variables without overfitting. It can account for non-additive interactions between these input variables. Random Forests can also be used for variable selection without being adversely affected by collinearities. ^ Random Forests can deal with the large-scale data sets without rigorous data preprocessing. It has robust variable importance ranking measure. Proposed is a novel variable selection method in context of Random Forests that uses the data noise level as the cut-off value to determine the subset of the important predictors. This new approach enhanced the ability of the Random Forests algorithm to automatically identify important predictors for complex data. The cut-off value can also be adjusted based on the results of the synthetic positive control experiments. ^ When the data set had high variables to observations ratio, Random Forests complemented the established logistic regression. This study suggested that Random Forests is recommended for such high dimensionality data. One can use Random Forests to select the important variables and then use logistic regression or Random Forests itself to estimate the effect size of the predictors and to classify new observations. ^ We also found that the mean decrease of accuracy is a more reliable variable ranking measurement than mean decrease of Gini. ^

A nested case-control study of radiation exposure and brain cancer incidence in the United States Air Force

A nested case-control study design was used to investigate the relationship between radiation exposure and brain cancer risk in the United States Air Force (USAF). The cohort consisted of approximately 880,000 men with at least 1 year of service between 1970 and 1989. Two hundred and thirty cases were identified from hospital discharge records with a diagnosis of primary malignant brain tumor (International Classification of Diseases, 9th revision, code 191). Four controls were exactly matched with each case on year of age and race using incidence density sampling. Potential career summary extremely low frequency (ELF) and microwave-radiofrequency (MWRF) radiation exposures were based upon the duration in each occupation and an intensity score assigned by an expert panel. Ionizing radiation (IR) exposures were obtained from personal dosimetry records.^ Relative to the unexposed, the overall age-race adjusted odds ratio (OR) for ELF exposure was 1.39, 95 percent confidence interval (CI) 1.03-1.88. A dose-response was not evident. The same was true for MWRF, although the OR = 1.59, with 95 percent CI 1.18-2.16. Excess risk was not found for IR exposure (OR = 0.66, 45 percent CI 0.26-1.72).^ Increasing socioeconomic status (SES), as identified by military pay grade, was associated with elevated brain tumor risk (officer vs. enlisted personnel age-race adjusted OR = 2.11, 95 percent CI 1.98-3.01, and senior officers vs. all others age-race adjusted OR = 3.30, 95 percent CI 2.0-5.46). SES proved to be an important confounder of the brain tumor risk associated with ELF and MWRF exposure. For ELF, the age-race-SES adjusted OR = 1.28, 95 percent CI 0.94-1.74, and for MWRF, the age-race-SES adjusted OR = 1.39, 95 percent CI 1.01-1.90.^ These results indicate that employment in Air Force occupations with potential electromagnetic field exposures is weakly, though not significantly, associated with increased risk for brain tumors. SES appeared to be the most consistent brain tumor risk factor in the USAF cohort. Other investigators have suggested that an association between brain tumor risk and SES may arise from differential access to medical care. However, in the USAF cohort health care is universally available. This study suggests that some factor other than access to medical care must underlie the association between SES and brain tumor risk. ^

Searching for the majority: algorithms of voluntary control.

Voluntary control of information processing is crucial to allocate resources and prioritize the processes that are most important under a given situation; the algorithms underlying such control, however, are often not clear. We investigated possible algorithms of control for the performance of the majority function, in which participants searched for and identified one of two alternative categories (left or right pointing arrows) as composing the majority in each stimulus set. We manipulated the amount (set size of 1, 3, and 5) and content (ratio of left and right pointing arrows within a set) of the inputs to test competing hypotheses regarding mental operations for information processing. Using a novel measure based on computational load, we found that reaction time was best predicted by a grouping search algorithm as compared to alternative algorithms (i.e., exhaustive or self-terminating search). The grouping search algorithm involves sampling and resampling of the inputs before a decision is reached. These findings highlight the importance of investigating the implications of voluntary control via algorithms of mental operations.

Effects of variable Gs expression on $\beta\sb2$-adrenergic receptor stimulated adenylyl cyclase response

An exact knowledge of the kinetic nature of the interaction between the stimulatory G protein (G$\sb{\rm s}$) and the adenylyl cyclase catalytic unit (C) is essential for interpreting the effects of Gs mutations and expression levels on cellular response to a wide variety of hormones, drugs, and neurotransmitters. In particular, insight as to the association of these proteins could lead to progress in tumor biology where single spontaneous mutations in G proteins have been associated with the formation of tumors (118). The question this work attempts to answer is whether the adenylyl cyclase activation by epinephrine stimulated $\beta\sb2$-adrenergic receptors occurs via G$\sb{\rm s}$ proteins by a G$\sb{\rm s}$ to C shuttle or G$\sb{\rm s}$-C precoupled mechanism. The two forms of activation are distinguishable by the effect of G$\sb{\rm s}$ levels on epinephrine stimulated EC50 values for cyclase activation.^ We have made stable transfectants of S49 cyc$\sp-$ cells with the gene for the $\alpha$ protein of G$\sb{\rm s}$ $(\alpha\sb{\rm s})$ which is under the control of the mouse mammary tumor virus LTR promoter (110). Expression of G$\sb{\rm s}\alpha$ was then controlled by incubation of the cells for various times with 5 $\mu$M dexamethasone. Expression of G$\sb{\rm s}\alpha$ led to the appearance of GTP shifts in the competitive binding of epinephrine with $\sp{125}$ICYP to the $\beta$-adrenergic receptors and to agonist dependent adenylyl cyclase activity. High expression of G$\sb{\rm s}\alpha$ resulted in lower EC50's for the adenylyl cyclase activity in response to epinephrine than did low expression. By kinetic modelling, this result is consistent with the existence of a shuttle mechanism for adenylyl cyclase activation by hormones.^ One item of concern that remains to be addressed is the extent to which activation of adenylyl cyclase occurs by a "pure" shuttle mechanism. Kinetic and biochemical experiments by other investigators have revealed that adenylyl cyclase activation, by hormones, may occur via a Gs-C precoupled mechanism (80, 94, 97). Activation of adenylyl cyclase, therefore, probably does not occur by either a pure "'Shuttle" or "Gs-C Precoupled" mechanism, but rather by a "Hybrid" mechanism. The extent to which either the shuttle or precoupled mechanism contributes to hormone stimulated adenylyl cyclase activity is the subject of on-going research. ^

Genes to blood pressure: The effects of variation in genes of the renin-angiotensin system on the hormonal and renal control of blood pressure

Objective. Essential hypertension affects 25% of the US adult population and is a leading contributor to morbidity and mortality. Because BP is a multifactorial phenotype that resists simple genetic analysis, intermediate phenotypes within the complex network of BP regulatory systems may be more accessible to genetic dissection. The Renin-Angiotensin System (RAS) is known to influence intermediate and long-term blood pressure regulation through alterations in vascular tone and renal sodium and fluid resorption. This dissertation examines associations between renin (REN), angiotensinogen (AGT), angiotensin-converting enzyme (ACE) and angiotensin II type 1 receptor (AT1) gene variation and interindividual differences in plasma hormone levels, renal hemodynamics, and BP homeostasis.^ Methods. A total of 150 unrelated men and 150 unrelated women, between 20.0 and 49.9 years of age and free of acute or chronic illness except for a history of hypertension (11 men and 7 women, all off medications), were studied after one week on a controlled sodium diet. RAS plasma hormone levels, renal hemodynamics and BP were determined prior to and during angiotensin II (Ang II) infusion. Individuals were genotyped by PCR for a variable number tandem repeat (VNTR) polymorphism in REN, and for the following restriction fragment length polymorphisms (RFLP): AGT M235T, ACE I/D, and AT1 A1166C. Associations between clinical measurements and allelic variation were examined using multiple linear regression statistical models.^ Results. Women homozygous for the AT1 1166C allele demonstrated higher intracellular levels of sodium (p = 0.044). Men homozygous for the AGT T235 allele demonstrated a blunted decrement in renal plasma flow in response to Ang II infusion (p = 0.0002). There were no significant associations between RAS gene variation and interindividual variation in RAS plasma hormone levels or BP.^ Conclusions. Rather than identifying new BP controlling genes or alleles, the study paradigm employed in this thesis (i.e., measured genes, controlled environments and interventions) may provide mechanistic insight into how candidate genes affect BP homeostasis. ^

A case-control study of bilateral compared with unilateral breast cancer

Approximately 10 to 15% of breast cancer patients develop a primary cancer in the contralateral breast. This study examined differences between women with unilateral compared with bilateral primary breast cancer. It focused on hormonal factors and family history, and evaluated the prevalences of invasive lobular histology and the replication error phenotype in the tumors. ^ Cases (n = 82) were patients at M.D. Anderson Cancer Center (MDACC) in Houston, Texas diagnosed with primary breast cancer in each breast between 1985 and 1994 inclusive. Controls (n = 82) were MDACC patients with primary cancer in a single breast diagnosed during the same interval, individually matched to cases. Data were obtained by in-person and/or telephone interview with the patient and/or proxy. Replication error phenotype was determined from archival tissue. ^ Diagnosis of breast, but not ovarian, cancer in a female first-degree relative (FFDR) was a strong risk factor for bilateral cancers. Cases had a significantly 3-fold higher excess of familial breast cancer than did controls (cases: O/E = 2.65, 95% CI = 1.85–3.69; controls: 0.86, 0.46–1.47; homogeneity: p = 0.00). Risk did not vary with menopausal status of the patient, but was greatest if a relative was diagnosed before age 45 (O/E = 38.9; 95% CI = 21.7–64.1). By implication, young first-degree relatives of patients with bilateral breast cancer are at very high risk of breast cancer themselves. Cases also had significantly fewer siblings than did controls. ^ Earlier menarche, and parity in the absence of lactation, were associated with bilateral cancers; age at menopause and parity with lactation were not. A history of alcohol consumption, particularly if heavy, carried a 3.4-fold risk (p = 0.03). The data suggested a slightly different pattern in risk factors according to menopausal status and interval between cancers. ^ Replication error phenotype was available for 59 probands. It was associated with bilateral cancers (particularly if diagnosed within one year of each other), increased age (p = 0.02) and negative nodal status. Invasive lobular histology was associated with bilateral disease but numbers were small. ^ These data suggest bilateral breast cancer arises in the context of a combination of familial and hormonal factors, and alcohol consumption. The relative importance of each factor may vary by age of the patient. ^

Locus of control as a predictor of students dropping out of high school

Education is related to health. In cross-sectional data, education level has been associated with physical functioning. Also, lower levels of education have been associated with health behaviors including smoking, alcohol use, and greater body weight. In school, students may benefit from greater exposed to health-related messages, while students who have dropped out may be more susceptible to influences regarding negative health behaviors such as smoking. ^ Improved school retention might improve long-term health outcomes. However, there is limited evidence regarding modifiable factors that predict likelihood of dropping out. Two likely psychosocial measures are locus of control and parent-child academic conversations. In the current study, data from two waves of a population-based longitudinal survey, the National Education Longitudinal Survey, were utilized to evaluate whether these two psychosocial measures could predict likelihood of dropping out, for students (n = 16,749) in tenth grade at 1990, with dropout status determined at 1992, while controlling for recognized sociodemographic predictors including parental income, parental education level, race/ethnicity, and sex. Locus of control was measured with the Pearlin Mastery Scale, and parent-child academic conversations were measured by three questions concerning course selection at school, school activities and events, and things the student studied in class. ^ In a logistic regression model, with the sociodemographic control measures entered in a first step before entry of the psychosocial measures in a second step, this study determined that lower levels of locus of control were associated with greater likelihood of dropping out after two years (odds ratio (OR) = 1.11, 95% confidence interval (CI) 108 to 1.15, p < .001), and two of the three parent-child academic discussion items were associated with greater likelihood of dropping out after two years (OR = 1.69, CI 1.48-1.93, p < .001; OR = 1.22, CI 1.05-1.41, p = .01; OR = 1.01, CI .88-1.15, p = .94). ^ It is possible that interventions aimed at improving locus of control, and aimed at building parent-child academic conversations, could lower the likelihood of students dropping out, and this in turn could yield improved heath behaviors and health status in the child's future. ^

Host risk factors for rifamycin-resistant clostridium difficile infection: A case control study

Objective. To evaluate the host risk factors associated with rifamycin-resistant Clostridium difficile (C. diff) infection in hospitalized patients compared to rifamycin-susceptible C.diff infection.^ Background. C. diff is the most common definable cause of nosocomial diarrhea affecting elderly hospitalized patients taking antibiotics for prolonged durations. The epidemiology of Clostridium difficile associated disease is now changing with the reports of a new hypervirulent strain causing hospital outbreaks. This new strain is associated with increased disease severity and mortality. The conventional therapy for C. diff includes metronidazole and vancomycin but high recurrence rates and treatment failures are now becoming a major concern. Rifamycin antibiotics are being developed as a new therapeutic option to treat C. diff infection after their efficacy was established in a few in vivo and in vitro studies. There are some recent studies that report an association between the hypervirulent strain and emerging rifamycin resistance. These findings assess the need for clinical studies to better understand the efficacy of rifamycin drugs against C. diff.^ Methods. This is a hospital-based, matched case-control study using de-identified data drawn from two prospective cohort studies involving C. diff patients at St Luke's Hospital. The C. diff isolates from these patients are screened for rifamycin resistance using agar dilution methods for minimum inhibitory concentrations (MIC) as part of Dr Zhi-Dong Jiang's study. Twenty-four rifamycin-rifamycin resistant C. diff cases were identified and matched with one rifamycin susceptible C. diff control on the basis of ± 10 years of age and hospitalization 30 days before or after the case. De-identified data for the 48 subjects was obtained from Dr Kevin Garey's clinical study at St Luke's Hospital enrolling C. diff patients. It was reviewed to gather information about host risk factors, outcome variables and relevant clinical characteristic.^ Results. Medical diagnosis at the time of admission (p = 0.0281) and history of chemotherapy (p = 0.022) were identified as a significant risk factor while hospital stay ranging from 1 week to 1 month and artificial feeding were identified as an important outcome variable (p = 0.072 and p = 0.081 respectively). Horn's Index assessing the severity of underlying illness and duration of antibiotics for cases and controls showed no significant difference.^ Conclusion. The study was a small project designed to identify host risk factors and understand the clinical implications of rifamycin-resistance. The study was underpowered and a larger sample size is needed to validate the results.^

Parental acculturation and adolescent HPV uptake among Hispanics: Results from the California Health Interview Survey

Background. The Centers for Disease Control and Prevention (CDC), the American Cancer Society (ACS), and the American College of Obstetricians and Gynecologists (ACOG) all recommend the HPV vaccine for girls 11-12. The vaccine has the potential to reduce cervical cancer disparities if it is used by populations that do not participate in screening. Evidence suggests that incidence and mortality are higher among Hispanic women compared to non-Hispanic white women because they do not participate in screening. Past literature has found that acculturation has a mixed effect on cervical cancer screening and immunization. Little is known about whether parental acculturation is associated with adolescent HPV vaccine uptake among Hispanics and the mechanisms through which acculturation may affect vaccine uptake.^ Aims. To examine the association between parental acculturation and adolescent HPV uptake among Hispanics in California and test the structural hypothesis of acculturation by determining if socioeconomic status (SES) and health care access mediate the association between acculturation and HPV vaccine uptake.^ Methods. Cross-sectional data from the 2007 California Health Interview Survey (CHIS) were used for bivariate and multivariate logistic regression analyses. The sample used for analysis included 1,090 Hispanic parents, with a daughter age 11-17, who answered questions about the HPV vaccine. Outcome variable of interest was HPV vaccine uptake (≥1dose). Independent variables of interest were language spoken at home (a proxy variable for acculturation), household income (percent of federal poverty level), education level, and health care access (combined measure of health insurance coverage and usual source of care).^ Results. Parents who spoke only English or English and Spanish in the home were more likely to get the HPV vaccine for their daughter than parents who only spoke Spanish (Odds Ratio [OR]: 0.55, 95% Confidence Interval [CI]: 0.31-0.98). When SES and health care access variables were added to the logistic regression model, the association between language acculturation and HPV vaccine uptake became non-significant (OR: 0.68, 95% CI: 0.35-1.29). Both income and health care access were associated with uptake. Parents with lower income or who did not have insurance and a usual source of care were less likely to have a vaccinated daughter.^ Discussion. Socioeconomic status and health care access have a more proximal effect on HPV vaccine uptake than parental language acculturation among Hispanics in California.^ Conclusion. This study found support for the structural hypothesis of acculturation and suggest that interventions focus on informing low SES parents who lack access to health care about programs that provide free HPV vaccines.^

Instrumental variable method for the causal relationship between soluble receptor for advanced glycation end-products (sRAGE) and risk of pancreatic cancer

This thesis project is motivated by the potential problem of using observational data to draw inferences about a causal relationship in observational epidemiology research when controlled randomization is not applicable. Instrumental variable (IV) method is one of the statistical tools to overcome this problem. Mendelian randomization study uses genetic variants as IVs in genetic association study. In this thesis, the IV method, as well as standard logistic and linear regression models, is used to investigate the causal association between risk of pancreatic cancer and the circulating levels of soluble receptor for advanced glycation end-products (sRAGE). Higher levels of serum sRAGE were found to be associated with a lower risk of pancreatic cancer in a previous observational study (255 cases and 485 controls). However, such a novel association may be biased by unknown confounding factors. In a case-control study, we aimed to use the IV approach to confirm or refute this observation in a subset of study subjects for whom the genotyping data were available (178 cases and 177 controls). Two-stage IV method using generalized method of moments-structural mean models (GMM-SMM) was conducted and the relative risk (RR) was calculated. In the first stage analysis, we found that the single nucleotide polymorphism (SNP) rs2070600 of the receptor for advanced glycation end-products (AGER) gene meets all three general assumptions for a genetic IV in examining the causal association between sRAGE and risk of pancreatic cancer. The variant allele of SNP rs2070600 of the AGER gene was associated with lower levels of sRAGE, and it was neither associated with risk of pancreatic cancer, nor with the confounding factors. It was a potential strong IV (F statistic = 29.2). However, in the second stage analysis, the GMM-SMM model failed to converge due to non- concaveness probably because of the small sample size. Therefore, the IV analysis could not support the causality of the association between serum sRAGE levels and risk of pancreatic cancer. Nevertheless, these analyses suggest that rs2070600 was a potentially good genetic IV for testing the causality between the risk of pancreatic cancer and sRAGE levels. A larger sample size is required to conduct a credible IV analysis.^

Weight-for-age percentile and its association to community acquired methicillin resistant Staphylococcus aureus among pediatric patients in Houston, TX

BACKGROUND: Weight has been implicated as a risk factor for symptomatic community-acquired methicillin resistant Staphylococcus Aureus (CA-MRSA). Information from Texas Children's Hospital (TCH) in Houston, TX was used to implement a case-control study to assess weight-for-age percentile (WFA), race and seasonal exposure as risk factors. ^ METHODS: A retrospective chart review to collect data from TCH was conducted covering the time period January 1st, 2008 to May 31st, 2011. Cases were confirmed and identified by the infectious disease department and were matched on a 1:1 ratio to controls that were seen by the emergency department for non-infected fractures from June 1st, 2008 to May 31st, 2011. Data abstraction was performed using TCH's electronic medical records (EMR) system (EPIC ®). ^ RESULTS: Of 702 CA-MRSA identified cases, ages 9 to 16.99, 564 (80.3%) had the variable `weight' present in their EMR, were not duplicates and not determined to be outliers. Cases were randomly matched to a pool of available controls (n=1864) according to age and gender, yielding 539 1:1 matched pairs (95.5% case matching success) with a total study sample size, N=1078. Case median age was 13.38 years with the majority being White (66.05%) and male (59.4%). Adjusted conditional logistic regression analysis of the matched pairs identified the following risk factors to presenting with CA-MRSA infection among pediatric patients, ages 9 to 16.99 years: a) Individual weight in the highest (75th-99.9th) WFA quartile (OR=1.36; 95% confidence interval [CI]=1.06-1.74; P= 0.016), b) Infection during summer months (OR: 1.69; 95% CI=1.2-2.38; P= 0.003), c) patients of African American race/ethnicity (OR= 1.48; 95% CI=1.13-1.95; P= 0.004). ^ CONCLUSIONS: Pediatric patients, 9 to 16.99 years of age, in the highest WFA quartile (75th-99.9th), or of African-American race had an associated increased risk of presenting with CA-MRSA infection. Furthermore, children in this population were at a higher risk of contracting CA-MRSA infection during the summer season.^

Estimates of hospital and physician costs of epilepsy in the United States for 1995 comparing the provider -based survey method and a patient -based medical charts and billing method

This investigation compares two different methodologies for calculating the national cost of epilepsy: provider-based survey method (PBSM) and the patient-based medical charts and billing method (PBMC&BM). The PBSM uses the National Hospital Discharge Survey (NHDS), the National Hospital Ambulatory Medical Care Survey (NHAMCS) and the National Ambulatory Medical Care Survey (NAMCS) as the sources of utilization. The PBMC&BM uses patient data, charts and billings, to determine utilization rates for specific components of hospital, physician and drug prescriptions. ^ The 1995 hospital and physician cost of epilepsy is estimated to be $722 million using the PBSM and $1,058 million using the PBMC&BM. The difference of $336 million results from $136 million difference in utilization and $200 million difference in unit cost. ^ Utilization. The utilization difference of $136 million is composed of an inpatient variation of $129 million, $100 million hospital and $29 million physician, and an ambulatory variation of $7 million. The $100 million hospital variance is attributed to inclusion of febrile seizures in the PBSM, $−79 million, and the exclusion of admissions attributed to epilepsy, $179 million. The former suggests that the diagnostic codes used in the NHDS may not properly match the current definition of epilepsy as used in the PBMC&BM. The latter suggests NHDS errors in the attribution of an admission to the principal diagnosis. ^ The $29 million variance in inpatient physician utilization is the result of different per-day-of-care physician visit rates, 1.3 for the PBMC&BM versus 1.0 for the PBSM. The absence of visit frequency measures in the NHDS affects the internal validity of the PBSM estimate and requires the investigator to make conservative assumptions. ^ The remaining ambulatory resource utilization variance is $7 million. Of this amount, $22 million is the result of an underestimate of ancillaries in the NHAMCS and NAMCS extrapolations using the patient visit weight. ^ Unit cost. The resource cost variation is $200 million, inpatient is $22 million and ambulatory is $178 million. The inpatient variation of $22 million is composed of $19 million in hospital per day rates, due to a higher cost per day in the PBMC&BM, and $3 million in physician visit rates, due to a higher cost per visit in the PBMC&BM. ^ The ambulatory cost variance is $178 million, composed of higher per-physician-visit costs of $97 million and higher per-ancillary costs of $81 million. Both are attributed to the PBMC&BM's precise identification of resource utilization that permits accurate valuation. ^ Conclusion. Both methods have specific limitations. The PBSM strengths are its sample designs that lead to nationally representative estimates and permit statistical point and confidence interval estimation for the nation for certain variables under investigation. However, the findings of this investigation suggest the internal validity of the estimates derived is questionable and important additional information required to precisely estimate the cost of an illness is absent. ^ The PBMC&BM is a superior method in identifying resources utilized in the physician encounter with the patient permitting more accurate valuation. However, the PBMC&BM does not have the statistical reliability of the PBSM; it relies on synthesized national prevalence estimates to extrapolate a national cost estimate. While precision is important, the ability to generalize to the nation may be limited due to the small number of patients that are followed. ^