Development of automated image analysis tools for verification of radiotherapy field accuracy with an electronic portal imaging device

The successful management of cancer with radiation relies on the accurate deposition of a prescribed dose to a prescribed anatomical volume within the patient. Treatment set-up errors are inevitable because the alignment of field shaping devices with the patient must be repeated daily up to eighty times during the course of a fractionated radiotherapy treatment. With the invention of electronic portal imaging devices (EPIDs), patient's portal images can be visualized daily in real-time after only a small fraction of the radiation dose has been delivered to each treatment field. However, the accuracy of human visual evaluation of low-contrast portal images has been found to be inadequate. The goal of this research is to develop automated image analysis tools to detect both treatment field shape errors and patient anatomy placement errors with an EPID. A moments method has been developed to align treatment field images to compensate for lack of repositioning precision of the image detector. A figure of merit has also been established to verify the shape and rotation of the treatment fields. Following proper alignment of treatment field boundaries, a cross-correlation method has been developed to detect shifts of the patient's anatomy relative to the treatment field boundary. Phantom studies showed that the moments method aligned the radiation fields to within 0.5mm of translation and 0.5$\sp\circ$ of rotation and that the cross-correlation method aligned anatomical structures inside the radiation field to within 1 mm of translation and 1$\sp\circ$ of rotation. A new procedure of generating and using digitally reconstructed radiographs (DRRs) at megavoltage energies as reference images was also investigated. The procedure allowed a direct comparison between a designed treatment portal and the actual patient setup positions detected by an EPID. Phantom studies confirmed the feasibility of the methodology. Both the moments method and the cross-correlation technique were implemented within an experimental radiotherapy picture archival and communication system (RT-PACS) and were used clinically to evaluate the setup variability of two groups of cancer patients treated with and without an alpha-cradle immobilization aid. The tools developed in this project have proven to be very effective and have played an important role in detecting patient alignment errors and field-shape errors in treatment fields formed by a multileaf collimator (MLC). ^

HUMAN PROPHASE CHROMOSOME UNIQUE BAND SEQUENCES; DEFINITION, CHARACTERIZATION, AND APPLICATION (CYTOGENETICS, IMAGE PROCESSING)

Extensive experience with the analysis of human prophase chromosomes and studies into the complexity of prophase GTG-banding patterns have suggested that at least some prophase chromosomal segments can be accurately identified and characterized independently of the morphology of the chromosome as a whole. In this dissertation the feasibility of identifying and analyzing specified prophase chromosome segments was thus investigated as an alternative approach to prophase chromosome analysis based on whole chromosome recognition. Through the use of prophase idiograms at the 850-band-stage (FRANCKE, 1981) and a comparison system based on the calculation of cross-correlation coefficients between idiogram profiles, we have demonstrated that it is possible to divide the 24 human prophase idiograms into a set of 94 unique band sequences. Each unique band sequence has a banding pattern that is recognizable and distinct from any other non-homologous chromosome portion.^ Using chromosomes 11p and 16 thru 22 to demonstrate unique band sequence integrity at the chromosome level, we found that prophase chromosome banding pattern variation can be compensated for and that a set of unique band sequences very similar to those at the idiogram level can be identified on actual chromosomes.^ The use of a unique band sequence approach in prophase chromosome analysis is expected to increase efficiency and sensitivity through more effective use of available banding information. The use of a unique band sequence approach to prophase chromosome analysis is discussed both at the routine level by cytogeneticists and at an image processing level with a semi-automated approach to prophase chromosome analysis. ^

Intensive care noise and mean arterial blood pressure in ELBW neonates

Objective. Loud noises in neonatal intensive care units (NICUs) may impede growth and development for extremely low birthweight (ELBW, < 1000 grams) newborns. The objective of this study was to measure the association between NICU sound levels and ELBW neonates' arterial blood pressure to determine whether these newborns experience noise-induced stress. ^ Methods. Noise and arterial blood pressure recordings were collected for 9 ELBW neonates during the first week of life. Sound levels were measured inside the incubator, and each subject's arterial blood pressures were simultaneously recorded for 15 minutes (at 1 sec intervals). Time series cross-correlation functions were calculated for NICU noise and mean arterial blood pressure (MABP) recordings for each subject. The grand mean noise-MABP cross-correlation was calculated for all subjects and for lower and higher birthweight groups for comparison. ^ Results. The grand mean noise-MABP cross-correlation for all subjects was mostly negative (through 300 sec lag time) and nearly reached significance at the 95% level at 111 sec lag (mean r = -0.062). Lower birthweight newborns (454-709 g) experienced significant decreases in blood pressure with increasing NICU noise after 145 sec lag (peak r = -0.074). Higher birthweight newborns had an immediate negative correlation with NICU sound levels (at 3 sec lag, r = -0.071), but arterial blood pressures increased to a positive correlation with noise levels at 197 sec lag (r = 0.075). ^ Conclusions. ELBW newborns' arterial blood pressure was influenced by NICU noise levels during the first week of life. Lower birthweight newborns may have experienced an orienting reflex to NICU sounds. Higher birthweight newborns experienced an immediate orienting reflex to increasing sound levels, but arterial blood pressure increased approximately 3 minutes after increases in noise levels. Increases in arterial blood pressure following increased NICU sound levels may result from a stress response to noise. ^

Validity and reliability of using MVP 4 Function Walk4Life digital pedometers to assess physical activity levels among preschool-aged Head Start children

The Surgeon General recommends preschoolers 3-5 years old accumulate 60 minutes of moderate-to-vigorous physical activity (MVPA) per day. However, there is limited data measuring physical activity (PA) and MVPA amongst this population. The purpose of this cross-sectional study is to determine the validity, reliability, and feasibility of using MVP 4 Function Walk4Life digital pedometers (MVP-4) in measuring MVPA among preschoolers using the newly modified direct observational technique, System for Observing Fitness Instruction Time-Preschool Version (SOFIT-P) as the gold standard. An ethnically diverse population of 3-5 year old underserved children were recruited from two Harris County Department of Education (HCDE) Head Start centers. For 2 days at baseline and 2 days at post-test, 75 children enrolled wore MVP-4 pedometers for approximately 6-hours per observation day and were observed using SOFIT-P during predominantly active times. Statistical analyses used Pearson "r" correlation coefficients to determine mean minutes of PA and MVPA, convergent and criterion validity, and reliability. Significance was set at p = <0.05. Feasibility was determined through process evaluation information collected during this study via observations from data collectors and teacher input. Results show mean minutes of PA and MVPA ranged between 30-42 and 11-14 minutes, respectively. Convergent validity comparing BMI percentiles with MVP-4 PA outcomes show no significance at pre-test; however, each measurement at post-test showed significance for MVPA (p = 0.0247, p = 0.0056), respectively. Criterion validity comparing percent MVPA time between SOFIT-P and MVP-4 pedometers was determined; however, results deemed insufficient due to inconsistency in observation times while using the newly developed SOFIT-P. Reliability measures show no significance at pre-test, yet show significant results for all PA outcomes at post-test (p = 0.001, p = 0.001, p = 0.0010, p = 0.003), respectively. Finally, MVP-4 pedometers lacked feasibility due to logistical barriers in design. Researchers feel the significant results at post-test are secondary to increased familiarity and more accurate placement of pedometers across time. Researchers suggest manufacturers of MVP-4 pedometers further modify the instrument for ease of use with this population, following which future studies ought to determine validity using objective measures or all-day direct observation techniques.^

Correlates of tobacco cessation counseling among Hispanic physicians in the US: a cross-sectional survey study.

BACKGROUND: Physician advice is an important motivator for attempting to stop smoking. However, physicians' lack of intervention with smokers has only modestly improved in the last decade. Although the literature includes extensive research in the area of the smoking intervention practices of clinicians, few studies have focused on Hispanic physicians. The purpose of this study was to explore the correlates of tobacco cessation counseling practices among Hispanic physicians in the US. METHODS: Data were collected through a validated survey instrument among a cross-sectional sample of self-reported Hispanic physicians practicing in New Mexico, and who were members of the New Mexico Hispanic Medical Society in the year 2001. Domains of interest included counseling practices, self-efficacy, attitudes/responsibility, and knowledge/skills. Returned surveys were analyzed to obtain frequencies and descriptive statistics for each survey item. Other analyses included: bivariate Pearson's correlation, factorial ANOVAs, and multiple linear regressions. RESULTS: Respondents (n = 45) reported a low level of compliance with tobacco control guidelines and recommendations. Results indicate that physicians' familiarity with standard cessation protocols has a significant effect on their tobacco-related practices (r = .35, variance shared = 12%). Self-efficacy and gender were both significantly correlated to tobacco related practices (r = .42, variance shared = 17%). A significant correlation was also found between self-efficacy and knowledge/skills (r = .60, variance shared = 36%). Attitudes/responsibility was not significantly correlated with any of the other measures. CONCLUSION: More resources should be dedicated to training Hispanic physicians in tobacco intervention. Training may facilitate practice by increasing knowledge, developing skills and, ultimately, enhancing feelings of self-efficacy.

Structure-function relation in retinoid regulated gene expression

Retinoids are known to inhibit proliferation of and induce terminal differentiation of many normal and transformed cells. It has been postulated that retinoids exert their effect by altering gene expression. HL-60 cells and macrophages both respond to retinoic acid action by the rapid induction of the enzyme tissue transglutaminase. The induction has been shown to be due to increased transcription of the transglutaminase gene. The first part of the dissertation studied the structure-function relationship of retinoid-regulated transglutaminase induction, differentiation and proliferation in HL-60 cells using retinoid analogs. The results indicated strict structural constraints and a strong structure-function correlation between transglutaminase induction and differentiation; those retinoids that induced transglutaminase also induced differentiation, those analogs that did not induce transglutaminase could not induce differentiation. The ability of the retinoids to induce transglutaminase in HL-60 cells was paralleled in macrophages. However, the antiproliferative effect of the retinoids displayed less stringent structural constraints than their differentiation- and transglutaminase-inducing properties. Specifically all the retinoids were able to inhibit proliferation to varying extents. It is concluded that the induction of transglutaminase and of differentiation by retinoids is mediated by receptors. While receptor mediation cannot be entirely ruled out, with the current data no definitive statement can be made about the antiproliferative activity of retinoids. Also, the concordance in the ability of the retinoids to induce transglutaminase and the ability to induce differentiation of HL-60 cells suggests that the former is an early response of the cells to retinoids and differentiation a later consequence on the same pathway. Using the induction of transglutaminase as an index of the direct, or primary, effect of retinoids on gene expression, the second part of the dissertation investigates, by 2D gel electrophoresis, the alteration in the rates of synthesis of other proteins in macrophages and HL-60 cells in response to short incubations with retinoic acid. Any changes in parallel with transglutaminase were taken to indicate proteins directly under the control of retinoic acid. It is concluded that retinoic acid regulates the expression of a circumscribed set of genes in a cell-specific manner. The results support the hypothesis that retinoids exert their multiple effects on myeloid cells, in part, by receptor-mediated alternations in gene expression. ^

Cell surface galactosyltransferase structure and function during mesenchymal cell migration

In order to more fully understand the function of surface GalTase on mesenchymal cells, anti-GalTase IgG was used to (a) examine the role of surface GalTase during mouse mesenchymal cell migration on laminin and fibronectin; (b) define the plasma membrane distribution of GalTase by indirect immunofluorescence on migrating cells; (c) quantitate the level of surface GalTase on migrating cells; and (d) determine whether GalTase is associated with the cytoskeleton.^ Results show that anti-GalTase IgG was able to inhibit migration (48-80% as compared to basal rate) when cells were migrating on laminin-containing matrices. Monovalent Fab fragments inhibited migration on laminin by 90% after 4 hours. On the other hand, anti-GalTase IgG had no effect on cells migrating on fibronectin. This illustrates the substrate specificity of GalTase mediated-migration. When anti-GalTase IgG was used to localize surface GalTase on cells migratory on laminin, the enzyme was restricted to the leading and trailing edges of the cell. Assays indicate that GalTase is elevated approximately 3-fold when cells are migrating on laminin-containing matrices as compared to migratory cells on plastic or fibronectin, or as compared to stationary cells on any substrate. Laminin appears to recruit GalTase from preexisting intracellular pools to the growing lamellipodia.^ Double-label indirect immunofluorescence studies indicate that there is an apparent co-localization between some of the surface GalTase and some actin filaments. This relationship was explored by extracting cells prelabeled with anti-GalTase IgG and quantitated by radiolabeled second antibodies. Results show that 79% of the surface GalTase is associated with the cytoskeleton (as judged by detergent insolubility) when monovalent antibodies (Fab) are used. However virtually all (80-100%) of the surface GalTase can be induced to associate with the cytoskeleton when cross-linked with bivalent antibodies. Furthermore, when cells in suspension are incubated with divalent antibodies, an additional 66% of the surface GalTase can be induced to associate with the cytoskeleton. The elevated levels of surface GalTase detectable on cells migrating on laminin also appear to be associated with the cytoskeleton.^ Several lines of evidence suggest that GalTase is associated with F-actin. Data suggest that laminin induces the expression of surface GalTase to the growing lamellipodia where it becomes associated with the cytoskeleton leading to cell spreading and migration. (Abstract shortened with permission of author.) ^

Analysis of endogenous retinoic acid receptor expression and function in murine melanoma cells

There have been numerous reports over the past several years on the ability of vitamin A analogs (retinoids) to modulate cell proliferation, malignant transformation, morphogenesis, and differentiation in a wide variety of cell types and organisms. Two families of nuclear retinoid-inducible, trans-acting, transcription-enhancing receptors that bear strong DNA sequence homology to thyroid and steroid hormone receptors have recently been discovered. The retinoic acid receptors (RARs) and retinoid X receptors (RXRs) each have at least three types designated $\alpha,$ $\beta,$ and $\gamma,$ which are encoded by separate genes and expressed in a tissue and cell type-specific manner. We have been interested in the mechanism by which retinoids inhibit tumor cell proliferation and induce differentiation. As a model system we have employed several murine melanoma cell lines (S91-C2, K1735P, and B16-F1), which are sensitive to the growth-inhibitory and differentiation-inducing effects of RA, as well as a RA-resistant subclone of one of the cell lines (S91-C154), in order to study the role of the nuclear RARs in these effects. The initial phase of this project consisted of the characterization of the expression pattern of the three known RAR and RXR types in the murine melanoma cell lines in order to determine whether any differences exist which may elucidate a role for any of the receptors in RA-induced growth inhibition and differentiation. The novel finding was made that the RAR-$\beta$ gene is rapidly induced from undetectable levels by RA treatment at the mRNA and protein level, and that the induction of RAR-$\beta$ by other biologically active retinoids correlated with their ability to inhibit the growth of the highly RA-sensitive S91-C2 cell line. This suggests a role for RAR-$\beta$ in the growth inhibiting effect of retinoids. The second phase of this project involves the stable expression of RAR-$\beta$ in the S91-C2 cells and the RAR-$\beta$ receptor-null cell line, K1735P. These studies have indicated an inverse correlation between RAR-$\beta$ expression and proliferation rate. ^

Cell surface $\beta$-1,4-galactosyltransferase function during invasion and metastasis

Metastasis is the complex process of tumor cell spread which is responsible for the majority of cancer-related deaths. Metastasis necessitates complex phenotypic changes, many of which are mediated by changes in the activities of cell surface molecules. One of these is cell surface $\beta$1,4-galactosyltransferase (GalTase), which is elevated on more highly metastatic cells. In this study, both molecular and biochemical methods were used to perturb and manipulate cell surface GalTase levels on K1735 murine melanoma cell lines in order to examine its function in metastasis.^ As expected, highly metastatic K1735 variants have higher cell surface GalTase than poorly metastatic variants. Stably transfected K1735 cell lines that overexpress surface GalTase were created. These cell lines were assayed for metastatic ability using an invasion chamber with Matrigel-coated filter inserts. Cells with increased surface GalTase were uniformly more invasive than neo transfected controls. With multiple cell lines, there was a direct correlation (r = 0.918) between surface GalTase activity and invasiveness. Homologous recombination was used to create K1735 cells with decreased levels of surface GalTase. These cells were uniformly less invasive than controls. Cell surface GalTase was inhibited using two different biochemical strategies. In both cases, inhibition of surface GalTase led to a decrease in in vivo metastatic ability of K1735 cells. This is the first direct experimental evidence addressing GalTase function in metastasis. These data provide several lines of independent evidence which show that cell surface GalTase facilitates invasion and metastasis. ^

Analysis of pp60$\sp{{\rm c}{-}src}$ and pp62$\sp{{\rm c}{-}yes}$ intracellular protein tyrosine kinase function in colon tumor cell growth regulation using herbimycin A, a tyrosine kinase specific inhibitor

Two approaches were utilized to investigate the role of pp60c-src activation in growth control of model colon tumor cell lines. The first approach involved analysis of pp60c-src activity in response to growth factor treatment to determine if transient activation of the protein was associated with ligand induced mitogenic signal transduction as occurs in non-colonic cell types. Activation of pp60c-src was detected using colon tumor cell lysates after treatment with platelet derived growth factor (PDGF). Activation of pp60c-src was also detected in response to epidermal growth factor (EGF) treatment using cellular lysates and intact cells. In contrast, down-regulation of purified pp60c-src occurred after incubation with EGF-treated EGFr immune complexes in vitro suggesting additional cellular events were potentially required for the stimulatory response observed in intact cells. The results demonstrated activation of pp60c-src in colon tumor cells in response to PDGF and EGF which is consistent with the role of the protein in mitogenic signal transduction in non-colonic cell types.^ The second approach used to study the role of pp60c-src activation in colonic cell growth control focused on analysis of the role of constitutive activation of the protein, which occurs in approximately 80% of colon tumors and cell lines, in growth control. These studies involved analysis of the effects of the tyrosine kinase specific inhibitor Herbimycin A (HA) on monolayer growth and pp60c-src enzymatic activity using model colon tumor cell lines. HA induced dose-dependent growth inhibition of all colon tumor cell lines examined possessing elevated pp60c-src activity. In HT29 cells the dose-dependent growth inhibition induced by HA correlated with dose-dependent pp60c-src inactivation. Inactivation of pp60c-src was shown to be an early event in response to treatment with HA which preceded induction of HT29 colon tumor cell growth inhibition. The growth effects of HA towards the colon tumor cells examined did not appear to be associated with induction of differentiation or a cytotoxic mechanism of action as changes in morphology were not detected in treated cells and growth inhibition (and pp60c-src inactivation) were reversible upon release from treatment with the compound. The results suggested the constitutive activation of pp60c-src functioned as a proliferative signal in colon tumor cells. Correlation between pp60c-src inactivation and growth inhibition was also observed using HA chemical derivatives confirming the role of tyrosine kinase inactivation by these compounds in inhibition of mitogenic signalling. In contrast, in AS15 cells possessing specific antisense mRNA mediated inactivation of pp60c-src, HA-induced inactivation of the related pp62c-yes tyrosine kinase, which is also activated during colon tumor progression, was not associated with induction of monolayer growth inhibition. These results suggested a function for the constitutively activated pp62c-yes protein in colon tumor cell proliferation which was different from that of activated pp60c-src. (Abstract shortened by UMI.) ^

The role of XPF in recombinational repair

The DNA repair gene, XPF, is implicated in numerous processes relating to maintenance of genomic stability. The experiments presented herein were designed to investigate the role of XPF in homologous recombination processes. Specifically, the role of XPF in plasmid-chromosome and intrachromosomal recombination was evaluated. To interrogate the mechanistic role of XPF in plasmid-chromosome recombination, a homologous gene targeting system at the APRT locus in Chinese Hamster Ovary (CHO) cells was used. The targeting vector is linearized within 900 base pairs of heterology, which generates a substrate with long, nonhomologous 3′-OH ends that must be efficiently processed, presumably by the Xpf/Ercc1 heterodimer, prior to a productive recombination event. These experiments demonstrated a significant decrease in the targeted gene recombination frequency and a significant change to the recombinant product distributions in XPF- and ERCC1-deficient CHO cell lines, which suggest that the Xpf/Ercc1 heterodimer is essential for strand invasion recombination involving the processing of long, nonhomologous tails. In order to evaluate the role of XPF in intrachromosomal recombination, direct APRT repeat constructs at the chromosomal APRT locus in XPF-proficient and XPF-deficient CHO cells were used in spontaneous and DSB-induced recombination experiments. A defect in intrachromosomal recombination was only shown for UV41-derived XPF -deficient CHO cells, which have a severe interstrand crosslinking phenotype. The results of these studies demonstrate a requirement for XPF function in both plasmid-chromosome and intrachromosomal recombination, specifically in removal of long, single-stranded 3′-OH DNA ends. In addition, these studies identified a correlation between the interstrand cross-linking phenotype and the intrachromosomal recombination phenotype of each CHO cell line, but did not demonstrate a correlation between the interstrand cross-linking phenotype and the plasmid-chromosome recombination phenotype of these CHO cell lines. ^

Correlation between dental care utilization and oral cavity cancer in a large sample of community-based United States residents

Cancer of the oral cavity and pharynx remains one of the ten leading causes of cancer death in the United States (US). Besides smoking and alcohol consumption, there are no well established risk factors. While poor dental care had been implicated, it is unknown if the lack of dental care, implying poor dental hygiene predisposes to oral cavity cancer. This study aimed to assess the relationship between dental care utilization during the past twelve months and the prevalence of oral cavity cancer. A cross-sectional design of the National Health Interview Survey of adult, non-institutionalized US residents (n=30,475) was used to assess the association between dental care utilization and self reported diagnosis of oral cavity cancer. Chi square statistic was used to examine the crude association between the predictor variable, dental care utilization and other covariates, while unconditional logistic regression was used to assess the relationship between oral cavity cancer and dental care utilization. There were statistically significant differences between those who utilized dental care during the past twelve months and those who did not with respect to education, income, age, marital status, and gender (p < 0.05), but not health insurance coverage (p = 0.53). Also, those who utilized dental care relative to those who did not were 65% less likely to present with oral cavity cancer, prevalence odds ratio (POR), 0.35, 95% Confidence Interval (CI), 0.12–0.98. Further, higher income advanced age, people of African heritage, and unmarried status were statistically significantly associated with oral cavity cancer, (p < 0.05), but health insurance coverage, alcohol use and smoking were not, p > 0.05. However, after simultaneously controlling for the relevant covariates, the association between dental care and oral cavity cancer did not attenuate nor persist. Thus, compared with those who did not use dental care, those who did wee 62% less likely to present with oral cavity cancer adjusted POR, 0.38, 95% CI, 0.13-1.10. Among US adults residing in community settings, use of dental care during the past twelve months did not significantly reduce the predisposition to oral cavity cancer. However, due to the nature of the data used in this study, which restricts temporal sequence, a large sample prospective study that may identify modifiable factors associated with oral cancer development namely poor dental care, is needed. ^

COX-2 expression in operable triple negative breast cancer: A hospital based cross-sectional study

Objectives. Triple Negative Breast Cancer (TNBC) lack expression of estrogen receptors (ER), progesterone receptors (PR), and absence of Her2 gene amplification. Current literature has identified TNBC and over-expression of cyclo-oxygenase-2 (COX-2) protein in primary breast cancer to be independent markers of poor prognosis in terms of overall and distant disease free survival. The purpose of this study was to compare COX-2 over-expression in TNBC patients to those patients who expressed one or more of the three tumor markers (i.e. ER, and/or PR, and/or Her2).^ Methods. Using a secondary data analysis, a cross-sectional design was implemented to examine the association of interest. Data collected from two ongoing protocols titled "LAB04-0657: a model for COX-2 mediated bone metastasis (Specific aim 3)" and "LAB04-0698: correlation of circulating tumor cells and COX-2 expression in primary breast cancer metastasis" was used for analysis. A sample of 125 female patients was analyzed using Chi-square tests and logistic regression models. ^ Results. COX-2 over-expression was present in 33% (41/125) and 28% (35/124) patients were identified as having TNBC. TNBC status was associated with elevated COX-2 expression (OR= 3.34; 95% CI= 1.40–8.22) and high tumor grade (OR= 4.09; 95% CI= 1.58–10.82). In a multivariable analysis, TNBC status was an important predictor of COX-2 expression after adjusting for age, menopausal status, BMI, and lymph node status (OR= 3.31; 95% CI: 1.26–8.67; p=0.01).^ Conclusion. TNBC is associated with COX-2 expression—a known marker of poor prognosis in patients with operable breast cancer. Replication of these results in a study with a larger sample size, or a future randomized clinical trial demonstrating an improved prognosis with COX-2 suppression in these patients would support this hypothesis.^

Selection bias and the cross-validation of regression models for prediction

Strategies are compared for the development of a linear regression model with stochastic (multivariate normal) regressor variables and the subsequent assessment of its predictive ability. Bias and mean squared error of four estimators of predictive performance are evaluated in simulated samples of 32 population correlation matrices. Models including all of the available predictors are compared with those obtained using selected subsets. The subset selection procedures investigated include two stopping rules, C$\sb{\rm p}$ and S$\sb{\rm p}$, each combined with an 'all possible subsets' or 'forward selection' of variables. The estimators of performance utilized include parametric (MSEP$\sb{\rm m}$) and non-parametric (PRESS) assessments in the entire sample, and two data splitting estimates restricted to a random or balanced (Snee's DUPLEX) 'validation' half sample. The simulations were performed as a designed experiment, with population correlation matrices representing a broad range of data structures.^ The techniques examined for subset selection do not generally result in improved predictions relative to the full model. Approaches using 'forward selection' result in slightly smaller prediction errors and less biased estimators of predictive accuracy than 'all possible subsets' approaches but no differences are detected between the performances of C$\sb{\rm p}$ and S$\sb{\rm p}$. In every case, prediction errors of models obtained by subset selection in either of the half splits exceed those obtained using all predictors and the entire sample.^ Only the random split estimator is conditionally (on $\\beta$) unbiased, however MSEP$\sb{\rm m}$ is unbiased on average and PRESS is nearly so in unselected (fixed form) models. When subset selection techniques are used, MSEP$\sb{\rm m}$ and PRESS always underestimate prediction errors, by as much as 27 percent (on average) in small samples. Despite their bias, the mean squared errors (MSE) of these estimators are at least 30 percent less than that of the unbiased random split estimator. The DUPLEX split estimator suffers from large MSE as well as bias, and seems of little value within the context of stochastic regressor variables.^ To maximize predictive accuracy while retaining a reliable estimate of that accuracy, it is recommended that the entire sample be used for model development, and a leave-one-out statistic (e.g. PRESS) be used for assessment. ^

A cross-sectional study of human symptomatology and residential formaldehyde concentrations

The cross-sectional study was performed to quantify the prevalence of symtomatology in residents of mobile homes as a function of indoor formaldehyde concentration. Formaldehyde concentrations were monitored for a seven hour period with an automated wet-chemical colorimetric analyzer. The health status of family members was ascertained by administration of questionnaires and physical exams. This is the first investigation to perform clinical assessments on residents undergoing concurrent exposure assessment in the home.^ Only 22.8% of households eligible for participation chose to cooperate. Monitoring data and health evaluations were obtained from 155 households in four Texas counties. A total of 428 residents (86.1%) were available for examination during the sampling hours. The study population included 45 infants, 126 children, and 257 adults.^ Formaldehyde concentration was not found to be significantly associated with increased risks for symptoms and signs of ocular irritation, dermal anomalies, or malaise. Three associations were identified that warrant further investigation. The relative odds associated with a doubling of formaldehyde concentration was significantly associated with parenchymal rales in adults and children. However, risk was modified by log respirable suspended particulate concentrations. Due to the presence of modification by a continuous variable, prevalence odds ratios (POR) and 95% confidence intervals (95% CI) for these associations are presented in tables. A doubling of formaldehyde concentration was also associated with an increased risk of perceived tightness in the chest in adults. Prevalence odds ratios are presented in a table due to effect modification by the average number of hours spent indoors on weekdays. Furthermore, a doubling of formaldehyde concentration was associated with an increased risk of drowsiness in children (POR = 2.60; 95% CI 1.04-6.51) and adults (POR = 1.94; 95% CI 1.20-3.14). ^