Development and testing of a procedure for systematically assigning gestational age for clinical and research use

A graphing method was developed and tested to estimate gestational ages pre-and postnatally in a consistent manner for epidemiological research and clinical purposes on feti/infants of women with few consistent prenatal estimators of gestational age. Each patient's available data was plotted on a single page graph to give a comprehensive overview of that patient. A hierarchical classification of gestational age determination was then applied in a systematic manner, and reasonable gestational age estimates were produced. The method was tested for validity and reliability on 50 women who had known dates for their last menstrual period or dates of conception, and multiple ultrasound examinations and other gestational age estimating measures. The feasibility of the procedure was then tested on 1223 low income women with few gestational age estimators. The graphing method proved to have high inter- and intrarater reliability. It was quick, easy to use, inexpensive, and did not require special equipment. The graphing method estimate of gestational age for each infant was tested against the last menstrual period gestational age estimate using paired t-Tests, F tests and the Kolmogorov-Smirnov test of similar populations, producing a 98 percent probability or better that the means and data populations were the same. Less than 5 percent of the infants' gestational ages were misclassified using the graphing method, much lower than the amount of misclassification produced by ultrasound or neonatal examination estimates. ^

Statistical characterization and development of summary measures of non-normal distributions of nuclear morphometry data from prostate cancer cells for use as prognostic indicators

Nuclear morphometry (NM) uses image analysis to measure features of the cell nucleus which are classified as: bulk properties, shape or form, and DNA distribution. Studies have used these measurements as diagnostic and prognostic indicators of disease with inconclusive results. The distributional properties of these variables have not been systematically investigated although much of the medical data exhibit nonnormal distributions. Measurements are done on several hundred cells per patient so summary measurements reflecting the underlying distribution are needed.^ Distributional characteristics of 34 NM variables from prostate cancer cells were investigated using graphical and analytical techniques. Cells per sample ranged from 52 to 458. A small sample of patients with benign prostatic hyperplasia (BPH), representing non-cancer cells, was used for general comparison with the cancer cells.^ Data transformations such as log, square root and 1/x did not yield normality as measured by the Shapiro-Wilks test for normality. A modulus transformation, used for distributions having abnormal kurtosis values, also did not produce normality.^ Kernel density histograms of the 34 variables exhibited non-normality and 18 variables also exhibited bimodality. A bimodality coefficient was calculated and 3 variables: DNA concentration, shape and elongation, showed the strongest evidence of bimodality and were studied further.^ Two analytical approaches were used to obtain a summary measure for each variable for each patient: cluster analysis to determine significant clusters and a mixture model analysis using a two component model having a Gaussian distribution with equal variances. The mixture component parameters were used to bootstrap the log likelihood ratio to determine the significant number of components, 1 or 2. These summary measures were used as predictors of disease severity in several proportional odds logistic regression models. The disease severity scale had 5 levels and was constructed of 3 components: extracapsulary penetration (ECP), lymph node involvement (LN+) and seminal vesicle involvement (SV+) which represent surrogate measures of prognosis. The summary measures were not strong predictors of disease severity. There was some indication from the mixture model results that there were changes in mean levels and proportions of the components in the lower severity levels. ^

Use of a hypomorphic allele of myogenin to analyze Myogenin-dependent processes in mouse development

Myogenin is a muscle-specific transcription factor essential for skeletal muscle differentiation. A severe reduction in the number of fused myotubes is seen in myogenin-null mice, and the expression of genes characteristic of differentiated skeletal muscle is reduced. Additionally, sternebrae defects are seen in myogenin-null mice, a secondary defect in the sternal cartilage precursors. Very little is known about the quantitative requirement for myogenin in muscle differentiation and thoracic skeletal development in vivo. In this thesis I describe experiments utilizing a mouse line harboring a hypomorphic allele of myogenin, generated by gene targeting techniques in embryonic stem cells. The nature of the hypomorphism was due to lowered levels of myogenin from this allele. In embryos homozygous for the hypomorphic allele, normal sternum formation and extensive muscle differentiation was observed. However, muscle hypoplasia and reduced muscle-specific gene expression were apparent in these embryos, and the mice were not viable after birth. These results suggest skeletal muscle differentiation is highly sensitive to the absolute amounts of myogenin, and reveal distinct threshold requirements for myogenin in skeletal muscle differentiation, sternum formation, and viability in vivo. The hypomorphic allele was utilized as a genetically sensitized background to identify other components of myogenin-mediated processes. Using a candidate gene approach I crossed null mutations in MEF2C and MRF4 into the hypomorphic background and examined whether these mutations affected muscle differentiation and skeleton formation in the myogenin hypomorph. Although MEF2C mutation did not affect any phenotypes seen in the hypomorphic background, MRF4 was observed to be an essential component of myogenin-mediated processes of thoracic skeletal development. Additionally, the hypomorphic allele was very sensitive to genetic effects, suggesting the existence of mappable genetic modifiers of the hypomorphic allele of myogenin. ^

Use of cognitive interviewing in the development of a Spanish language genetic knowledge instrument

Study purpose. Genetic advances are significantly impacting healthcare, yet recent studies of ethnic group participation in genetic services demonstrate low utilization rates by Latinos. Limited genetic knowledge is a major barrier. The purpose of this study was to field test items in a Spanish-language instrument that will be used to measure genetic knowledge relevant to type 2 diabetes among members of the ethnically heterogeneous U.S. Latino community. Accurate genetic knowledge measurement can provide the foundation for interventions to enhance genetic service utilization. ^ Design. Three waves of cognitive interviews were conducted in Spanish to field test 44 instrument items Thirty-six Latinos, with 12 persons representative of Mexican, Central and South American, and Cuban heritage participated, including 7 males and 29 females between 22 and 60 years of age; 17 participants had 12 years or less of education. ^ Methods. Text narratives from transcriptions of audiotaped interviews were qualitatively analyzed using a coding strategy to indicate potential sources of response error. Through an iterative process of instrument refinement, codes that emerged from the data were used to guide item revisions at the conclusion of each phase; revised items were examined in subsequent interview waves. ^ Results. Inter-cultural and cross-cultural themes associated with difficulties in interpretation and grammatical structuring of items were identified; difficulties associated with comprehension reflected variations in educational level. Of the original 44 items, 32 were retained, 89% of which were revised. Six additional items reflective of cultural knowledge were constructed, resulting in a 38-item instrument. ^ Conclusions. Use of cognitive interviewing provided a valuable tool for detecting both potential sources of response error and cultural variations in these sources. Analysis of interview data guided successive instrument revisions leading to improved item interpretability and comprehension. Although testing in a larger sample will be essential to test validity and reliability, the outcome of field testing suggests initial content validity of a Spanish-language instrument to measure genetic knowledge relative to type 2 diabetes. ^ Keywords. Latinos, genetic knowledge, instrument development, cognitive interviewing ^

Development and Implementation of the Use of Optically Stimulated Luminescent Detectors in the Radiological Physics Center Anthropomorphic Quality Assurance Phantoms

The Radiological Physics Center (RPC) uses both on-site and remote reviews to credential institutions for participation in clinical trials. Anthropomorphic quality assurance (QA) phantoms are one tool the RPC uses to remotely audit institutions, which include thermoluminescent dosimeters (TLDs) and radiochromic film. The RPC desires to switch from TLD as the absolute dosimeter in the phantoms, to optically stimulated luminescent dosimeters (OSLDs), but a problem lies in the angular dependence exhibited by the OSLD. The purpose of this study was to characterize the angular dependence of OSLD and establish a correction factor if necessary, to provide accurate dosimetric measurements as a replacement for TLD in the QA phantoms. A 10 cm diameter high-impact polystyrene spherical phantom was designed and constructed to hold an OSLD to study the angular response of the dosimeter under the simplest of circumstances for both coplanar and non-coplanar treatment deliveries. OSLD were irradiated in the spherical phantom, and the responses of the dosimeter from edge-on angles were normalized to the response when irradiated with the beam incident normally on the surface of the dosimeter. The average normalized response was used to establish an angular correction factor for 6 MV and 18 coplanar treatments, and for 6 MV non-coplanar treatments specific to CyberKnife. The RPC pelvic phantom dosimetry insert was modified to hold OSLD, in addition to the TLD, adjacent to the planes of film. Treatment plans of increasing angular beam delivery were developed, three in Pinnacle v9.0 (4-field box, IMRT, and VMAT) and one in Accuray’s MultiPlan v3.5.3 (CyberKnife). The plans were delivered to the pelvic phantom containing both TLD and OSLD in the target volume. The pelvic phantom was also sent to two institutions to be irradiated as trials, one delivering IMRT, and the other a CyberKnife treatment. For the IMRT deliveries and the two institution trials, the phantom also included film in the sagittal and coronal planes. The doses measured from the TLD and OSLD were calculated for each irradiation, and the angular correction factors established from the spherical phantom irradiations were applied to the OSLD dose. The ratio of the TLD dose to the angular corrected OSLD dose was calculated for each irradiation. The corrected OSLD dose was found to be within 1% of the TLD measured dose for all irradiations, with the exception of the in-house CyberKnife deliveries. The films were normalized to both TLD measured dose and the corrected OSLD dose. Dose profiles were obtained and gamma analysis was performed using a 7%/4 mm criteria, to compare the ability of the OSLD, when corrected for the angular dependence, to provide equivalent results to TLD. The results of this study indicate that the OSLD can effectively be used as a replacement for TLD in the RPC’s anthropomorphic QA phantoms for coplanar treatment deliveries when a correction is applied for the dosimeter’s angular dependence.

Development and evaluation of a video-based modeling strategy for the dissemination phase of a school health tobacco -use prevention program

Even the best school health education programs will be unsuccessful if they are not disseminated effectively in a manner that encourages classroom adoption and implementation. This study involved two components: (1) the development of a videotape intervention to be used in the dissemination phase of a 4-year, NCI-funded diffusion study and (2) the evaluation of that videotape intervention strategy in comparison with a print (information transfer) strategy. Conceptualization has been guided by Social Learning Theory, Diffusion Theory, and communication theory. Additionally, the PRECEDE Framework has been used. Seventh and 8th grade classroom teachers from Spring Branch Independent School District in west Houston participated in the evaluation of the videotape and print interventions using a 57-item preadoption survey instrument developed by the UT Center for Health Promotion Research and Development. Two-way ANOVA was used to study individual score differences for five outcome variables: Total Scale Score (comprised of 57 predisposing, enabling, and reinforcing items), Adoption Characteristics Subscale, Attitude Toward Innovation Subscale, Receptivity Toward Innovation, and Reinforcement Subscale. The aim of the study is to compare the effect upon score differences of video and print interventions alone and in combination. Seventy-three 7th and 8th grade classroom teachers completed the study providing baseline and post-intervention measures on factors related to the adoption and implementation of tobacco-use prevention programs. Two-way ANOVA, in relation to the study questions, found significant scoring differences for those exposed to the videotape intervention alone for both the Attitude Toward Innovation Subscale and the Receptivity to Adopt Subscale. No significant results were found to suggest that print alone influences favorable scoring differences between baseline and post-intervention testing. One interaction effect was found suggesting video and print combined are more effective for influencing favorable scoring differences for the Reinforcement for the Adoption Subscale.^ This research is unique in that it represents a newly emerging field in health promotion communications research with implications for Social Learning Theory, Diffusion Theory, and communication science that are applicable to the development of improved school health interventions. ^