Outcomes of safety and effectiveness in a multicenter randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy.

BACKGROUND: Whole-body hypothermia reduced the frequency of death or moderate/severe disabilities in neonates with hypoxic-ischemic encephalopathy in a randomized, controlled multicenter trial. OBJECTIVE: Our goal was to evaluate outcomes of safety and effectiveness of hypothermia in infants up to 18 to 22 months of age. DESIGN/METHODS: A priori outcomes were evaluated between hypothermia (n = 102) and control (n = 106) groups. RESULTS: Encephalopathy attributable to causes other than hypoxia-ischemia at birth was not noted. Inotropic support (hypothermia, 59% of infants; control, 56% of infants) was similar during the 72-hour study intervention period in both groups. Need for blood transfusions (hypothermia, 24%; control, 24%), platelet transfusions (hypothermia, 20%; control, 12%), and volume expanders (hypothermia, 54%; control, 49%) was similar in the 2 groups. Among infants with persistent pulmonary hypertension (hypothermia, 25%; control, 22%), nitric-oxide use (hypothermia, 68%; control, 57%) and placement on extracorporeal membrane oxygenation (hypothermia, 4%; control, 9%) was similar between the 2 groups. Non-central nervous system organ dysfunctions occurred with similar frequency in the hypothermia (74%) and control (73%) groups. Rehospitalization occurred among 27% of the infants in the hypothermia group and 42% of infants in the control group. At 18 months, the hypothermia group had 24 deaths, 19 severe disabilities, and 2 moderate disabilities, whereas the control group had 38 deaths, 25 severe disabilities, and 1 moderate disability. Growth parameters were similar between survivors. No adverse outcomes were noted among infants receiving hypothermia with transient reduction of temperature below a target of 33.5 degrees C at initiation of cooling. There was a trend in reduction of frequency of all outcomes in the hypothermia group compared with the control group in both moderate and severe encephalopathy categories. CONCLUSIONS: Although not powered to test these secondary outcomes, whole-body hypothermia in infants with encephalopathy was safe and was associated with a consistent trend for decreasing frequency of each of the components of disability.

A process evaluation of a health literacy intervention targeting pediatric providers' communication skills at the Texas Children's Health Plan

Background. Health literacy is an important determinant for quality health care, and affects communication between patients and physicians. Poor communication may result in negative effects in health. Improved communication between patients and physicians could positively affect health outcomes. Communication skills are teachable.^ Objectives. (1) to evaluate the process involved in the design and implementation of a health literacy intervention targeting pediatric providers’ communication skills at the Texas Children’s Health Plan in Houston, Texas; and (2) to describe lessons learned from this process that may be used in future attempts to address the issue of health literacy and health communication. ^ Design/methods. The process evaluation of the implementation of a health literacy strategy at the Texas Children’s Health Plan (TCHP) consisted of a critical analysis of all documents and minutes from meetings of the team of investigators. It also involved a secondary analysis of data collected between December 2006 and June 2007. Descriptive statistics, paired t-test and Wilcoxon-signed-rank test were employed in analyzing the data. This information was complemented with a limited review of existing literature on communication skills training programs. ^ Results. The design of the educational intervention followed recommendations from experts in the field of health literacy. The delivery of the intervention was possible and benefited from existing resources and logistics within the TCHP. Very few targeted providers participated in two offerings of the workshop (6.6% and 1.7% respectively). After the educational intervention, providers showed increased knowledge of health literacy facts and its effects in health (p=0.001); increased awareness of the low health literacy problem (p=0.003); increased expectations for change in practice (p=0.002), and intent to use health literacy strategies for communication immediately following the intervention (p=0.001). Low participation indicated the need for further investigation of barriers to, and means for successful implementation of programs aimed to improving health communication. ^ Conclusions. A short, focused intervention utilizing health literacy strategies for communication appeared effective in increasing knowledge and intentions for change in a small group of pediatric providers. ^

A study of the association between timing of solid food introduction in infants and overweight and obesity in pre-school aged children in NHANES 2003-2008

Background. Previous studies suggest an association between timing of introduction of solid food and increased risk of obesity in pre-school aged children, but no study included a representative sample of US children. We sought to examine whether there was any association between the timing of solid food introduction and overweight/obesity in pre-school aged children. Design/methods. Cross-sectional study of a nationally representative sample (N=2050) of US children aged 2 to 5 years with information on infant feeding practices and measured weight and height from the National Health and Nutrition Examination Survey 2003–2008. The main outcome measure was BMI for age and sex ≥ 85th percentile. The main exposure was timing of solid food introduction at < 4, 4–5, or ≥ 6 months of age. Binomial logistic regression was used in the analysis controlling for child's sex, birth weight and breastfeeding status as well as maternal age at birth, smoking status and socio-demographic variables. Results. Two thousand and fifty children were included in the sample; 51% male and 49% female; 57.1% Non-Hispanic White, 21.9% Hispanic, 14.0% Non-Hispanic Black, and 7% other race/ethnicity. Twenty-two percent of the children were overweight or obese. Sixty-nine percent were breastfed or fed breast milk at birth and 36% continued breastfeeding for ≥ six months. Solid foods were introduced before 4 months of age for 11.2% of the children; 30.3% received solid foods between 4 to 5 months; with 58.6% receiving solid foods at 6 months or later. Timing of solid food introduction was not associated with weight status (OR= 1.36, 95% CI [0.83–2.24]). Formula-fed infants and infants breastfed for < 4 months had increased odds of overweight and obesity (OR=1.54, 95% CI [1.05–2.27] and OR= 1.60, 95% CI [1.05–2.44], respectively) when compared to infants breastfed for ≥ 6 months. Conclusion. Timing of solid food introduction was not associated with weight status in a national sample of US children ages 2 to 5 years. More focus should be placed on promoting breastfeeding and healthy infant feeding practices as strategies to prevent obesity in children. ^

Assessing the Influence of Brain-based Instructional Methods and Its Impact on Systemic Change for Learning Communities

Background: As scholars who prepare future school leaders to be innovative instructional leaders for their learning communities, we are on the verge of a curriculum design revolution. The application of brain research findings promotes educational reform efforts to systemically change the way in which children experience school. However, most educators, school leaders, board members, and policy makers are ill prepared to reconsider the implications for assessment, pedagogy, school climate, daily schedules, and use of technology. This qualitative study asked future school leaders to reconsider how school leadership preparedness programs prepared them to become instructional leaders for the 21st century. The findings from this study will enhance the field of school leadership, challenging the current emphasis placed on standardized testing, traditional school calendars, assessments, monocultural instructional methods, and meeting the needs of diverse learning communities. [See PDF for complete abstract]

Design and evaluation of the parent education component of a comprehensive violence prevention project in middle schools

Low parental monitoring is related to youth risk behaviors such as delinquency and aggression. The purpose of this dissertation was to describe the development and evaluation of a parent education intervention to increase parental monitoring in Hispanic parents of middle school children.^ The first study described the process of intervention mapping as used to develop Padres Trabajando por la Paz, a newsletter intervention for parents. Using theory, empirical literature, and information from the target population, performance objectives and determinants for monitoring were defined. Learning objectives were specified and a staged social-cognitive approach was used to develop methods and strategies delivered through newsletters.^ The second study examined the outcomes of a randomized trial of the newsletter intervention. Outcome measures consisted of a general measure of monitoring, parent and child reports of monitoring behaviors targeted by the intervention, and psychosocial determinants of monitoring (self-efficacy, norms, outcome expectancies, knowledge, and beliefs). Seventy-seven parents completed the randomized trial, half of which received four newsletters over an eight-week period. Results revealed a significant interaction effect for baseline and treatment for parent's reports of norms for monitoring (p =.009). Parents in the experimental condition who scored low at baseline reported increased norms for monitoring at follow-up. A significant interaction effect for child reports of parental monitoring behaviors (p =.04) reflected an small increase across baseline levels in the experimental condition and decreases for the control condition at higher baseline scores. Both groups of parents reported increased levels of monitoring at follow-up. No other outcome measures varied significantly by condition.^ The third study examined the relationship between the psychosocial determinants of parental monitoring and parental monitoring behaviors in the study population. Weak evidence for a relationship between outcome expectancies and parental monitoring behaviors suggests further research in the area utilizing stronger empirical models such as longitudinal design and structural equation modeling.^ The low-cost, minimal newsletter intervention showed promise for changing norms among Hispanic parents for parental monitoring. In light of the importance of parental monitoring as a protective factor for youth health risk behaviors, more research needs to be done to develop and evaluate interventions to increase parental monitoring. ^

Design and analysis for three level hierarchical structures with count response

In numerous intervention studies and education field trials, random assignment to treatment occurs in clusters rather than at the level of observation. This departure of random assignment of units may be due to logistics, political feasibility, or ecological validity. Data within the same cluster or grouping are often correlated. Application of traditional regression techniques, which assume independence between observations, to clustered data produce consistent parameter estimates. However such estimators are often inefficient as compared to methods which incorporate the clustered nature of the data into the estimation procedure (Neuhaus 1993).1 Multilevel models, also known as random effects or random components models, can be used to account for the clustering of data by estimating higher level, or group, as well as lower level, or individual variation. Designing a study, in which the unit of observation is nested within higher level groupings, requires the determination of sample sizes at each level. This study investigates the design and analysis of various sampling strategies for a 3-level repeated measures design on the parameter estimates when the outcome variable of interest follows a Poisson distribution. ^ Results study suggest that second order PQL estimation produces the least biased estimates in the 3-level multilevel Poisson model followed by first order PQL and then second and first order MQL. The MQL estimates of both fixed and random parameters are generally satisfactory when the level 2 and level 3 variation is less than 0.10. However, as the higher level error variance increases, the MQL estimates become increasingly biased. If convergence of the estimation algorithm is not obtained by PQL procedure and higher level error variance is large, the estimates may be significantly biased. In this case bias correction techniques such as bootstrapping should be considered as an alternative procedure. For larger sample sizes, those structures with 20 or more units sampled at levels with normally distributed random errors produced more stable estimates with less sampling variance than structures with an increased number of level 1 units. For small sample sizes, sampling fewer units at the level with Poisson variation produces less sampling variation, however this criterion is no longer important when sample sizes are large. ^ 1Neuhaus J (1993). “Estimation efficiency and Tests of Covariate Effects with Clustered Binary Data”. Biometrics , 49, 989–996^

Design and implementation of a multicriteria medical decision support system for diagnosis and treatment

Health care providers face the problem of trying to make decisions with inadequate information and also with an overload of (often contradictory) information. Physicians often choose treatment long before they know which disease is present. Indeed, uncertainty is intrinsic to the practice of medicine. Decision analysis can help physicians structure and work through a medical decision problem, and can provide reassurance that decisions are rational and consistent with the beliefs and preferences of other physicians and patients. ^ The primary purpose of this research project is to develop the theory, methods, techniques and tools necessary for designing and implementing a system to support solving medical decision problems. A case study involving “abdominal pain” serves as a prototype for implementing the system. The research, however, focuses on a generic class of problems and aims at covering theoretical as well as practical aspects of the system developed. ^ The main contributions of this research are: (1) bridging the gap between the statistical approach and the knowledge-based (expert) approach to medical decision making; (2) linking a collection of methods, techniques and tools together to allow for the design of a medical decision support system, based on a framework that involves the Analytic Network Process (ANP), the generalization of the Analytic Hierarchy Process (AHP) to dependence and feedback, for problems involving diagnosis and treatment; (3) enhancing the representation and manipulation of uncertainty in the ANP framework by incorporating group consensus weights; and (4) developing a computer program to assist in the implementation of the system. ^

Using GIS methods to assess the occurrence of neural tube defect births by residential proximity at conception to hazardous waste sites

In the United States, approximately 4,000 pregnancies each year are affected by the two most common birth defects, spina bifida and anencephaly. Studies have shown that exposure to environmental chemicals before and after conception may adversely affect reproduction by inducing cell death or dysfunction, which leads to infertility, fetal loss, lowered weight at birth, or birth anomalies in the offspring. The objective of the study was to evaluate the relationship between Neural Tube Defect births and residence at conception in proximity to hazardous waste sites in the Texas-Mexico border region between 1993 and 2000. ^ The study design was a nested matched case-control and utilized secondary data from a project, “The role of chemical and biological factors in the etiology of neural tube birth defects births along the Texas-Mexico Border” (Irina Cech, Principal Investigator). Geographic Information Systems (GIS) database methods were used to compare Neural Tube Defects cases to controls on status of conception residence occurring within a one-mile radius from hazardous waste sites, as compared to conception residence further away. Information on the exposures was obtained from the OnTarget Database and Environment Protection Agency website. Conditional logistic regression was used for the matched case-control study to investigate the relationship between an outcome of being a case or a control and proximity to hazardous waste sites. ^ The result of the study showed a 36 percent non-significant increased risk of having an NTD birth associated with maternal proximity to abandoned hazardous waste sites (95% CI = 0.62–3.02). In addition, there was a 24% non-significant elevated risk of having an NTD birth when living in proximity to air pollutant sites than when living further away (95% CI = 0.67–2.32). Although this study did not find statistically significant associations, it will expand on the existing knowledge of the relationship between NTD and proximity to hazardous waste sites. ^

Specialized managed care for children with cystic fibrosis: Resource use patterns and rate design for a high cost Medicaid population

Objective. This research study had two goals: (1) to describe resource consumption patterns for Medi-Cal children with cystic fibrosis, and (2) to explore the feasibility from a rate design perspective of developing specialized managed care plans for such a special needs population.^ Background. Children with special health care needs (CSHN) comprise about 2% of the California Medicaid pediatric population. CSHN have rare but serious health problems, such as cystic fibrosis. Medicaid programs, including Medi-Cal, are enrolling more and more beneficiaries in managed care to control costs. CSHN, however, do not fit the wellness model underlying most managed care plans. Child health advocates believe that both efficiency and quality will suffer if CSHN are removed from regionalized special care centers and scattered among general purpose plans. They believe that CSHN should be "carved out" from enrollment in general plans. One alternative is the Specialized Managed Care Plan, tailored for CSHN.^ Methods. The study population consisted of children under age 21 with CF who were eligible for Medi-Cal and California Children's Services program (CCS) during 1991. Health Care Financing Administration (HCFA) Medicaid Tape-to-Tape data were analyzed as part of a California Children's Hospital Association (CCHA) project.^ Results. Mean Medi-Cal expenditures per month enrolled were $2,302 for 457 CF children, compared to about \$1,270 for all 47,000 CCS special needs children and roughly $60 for almost 2.6 million ``regular needs'' children. For CF children, inpatient care (80\%) and outpatient drugs (9\%) were the major cost drivers, with {\it all\/} outpatient visits comprising only 2\% of expenditures. About one-third of CF children were eligible due to AFDC (Aid to Families with Dependent Children). Age group explained about 17\% of all expenditure variation. Regression analysis was used to select the best capitation rate structure (rate cells by age and eligibility group). Sensitivity analysis estimated moderate financial risk for a statewide plan (360 enrollees), but severe risk for single county implementation due to small numbers of children.^ Conclusions. Study results support the carve out of CSHN due to unique expenditure patterns. The Specialized Managed Care Plan concept appears feasible from a rate design perspective given sufficient enrollees. ^

Statistical issues on studies of mixed longitudinal design

Mixed longitudinal designs are important study designs for many areas of medical research. Mixed longitudinal studies have several advantages over cross-sectional or pure longitudinal studies, including shorter study completion time and ability to separate time and age effects, thus are an attractive choice. Statistical methodology used in general longitudinal studies has been rapidly developing within the last few decades. Common approaches for statistical modeling in studies with mixed longitudinal designs have been the linear mixed-effects model incorporating an age or time effect. The general linear mixed-effects model is considered an appropriate choice to analyze repeated measurements data in longitudinal studies. However, common use of linear mixed-effects model on mixed longitudinal studies often incorporates age as the only random-effect but fails to take into consideration the cohort effect in conducting statistical inferences on age-related trajectories of outcome measurements. We believe special attention should be paid to cohort effects when analyzing data in mixed longitudinal designs with multiple overlapping cohorts. Thus, this has become an important statistical issue to address. ^ This research aims to address statistical issues related to mixed longitudinal studies. The proposed study examined the existing statistical analysis methods for the mixed longitudinal designs and developed an alternative analytic method to incorporate effects from multiple overlapping cohorts as well as from different aged subjects. The proposed study used simulation to evaluate the performance of the proposed analytic method by comparing it with the commonly-used model. Finally, the study applied the proposed analytic method to the data collected by an existing study Project HeartBeat!, which had been evaluated using traditional analytic techniques. Project HeartBeat! is a longitudinal study of cardiovascular disease (CVD) risk factors in childhood and adolescence using a mixed longitudinal design. The proposed model was used to evaluate four blood lipids adjusting for age, gender, race/ethnicity, and endocrine hormones. The result of this dissertation suggest the proposed analytic model could be a more flexible and reliable choice than the traditional model in terms of fitting data to provide more accurate estimates in mixed longitudinal studies. Conceptually, the proposed model described in this study has useful features, including consideration of effects from multiple overlapping cohorts, and is an attractive approach for analyzing data in mixed longitudinal design studies.^

Design, Calibration, and Evaluation of Depth-of-Interaction-Capable PET Detector Modules

High-resolution, small-bore PET systems suffer from a tradeoff between system sensitivity, and image quality degradation. In these systems long crystals allow mispositioning of the line of response due to parallax error and this mispositioning causes resolution blurring, but long crystals are necessary for high system sensitivity. One means to allow long crystals without introducing parallax errors is to determine the depth of interaction (DOI) of the gamma ray interaction within the detector module. While DOI has been investigated previously, newly available solid state photomultipliers (SSPMs) well-suited to PET applications and allow new modules for investigation. Depth of interaction in full modules is a relatively new field, and so even if high performance DOI capable modules were available, the appropriate means to characterize and calibrate the modules are not. This work presents an investigation of DOI capable arrays and techniques for characterizing and calibrating those modules. The methods introduced here accurately and reliably characterize and calibrate energy, timing, and event interaction positioning. Additionally presented is a characterization of the spatial resolution of DOI capable modules and a measurement of DOI effects for different angles between detector modules. These arrays have been built into a prototype PET system that delivers better than 2.0 mm resolution with a single-sided-stopping-power in excess of 95% for 511 keV g's. The noise properties of SSPMs scale with the active area of the detector face, and so the best signal-to-noise ratio is possible with parallel readout of each SSPM photodetector pixel rather than multiplexing signals together. This work additionally investigates several algorithms for improving timing performance using timing information from multiple SSPM pixels when light is distributed among several photodetectors.

Adaptive clinical trial design for targeted therapy development

The development of targeted therapy involve many challenges. Our study will address some of the key issues involved in biomarker identification and clinical trial design. In our study, we propose two biomarker selection methods, and then apply them in two different clinical trial designs for targeted therapy development. In particular, we propose a Bayesian two-step lasso procedure for biomarker selection in the proportional hazards model in Chapter 2. In the first step of this strategy, we use the Bayesian group lasso to identify the important marker groups, wherein each group contains the main effect of a single marker and its interactions with treatments. In the second step, we zoom in to select each individual marker and the interactions between markers and treatments in order to identify prognostic or predictive markers using the Bayesian adaptive lasso. In Chapter 3, we propose a Bayesian two-stage adaptive design for targeted therapy development while implementing the variable selection method given in Chapter 2. In Chapter 4, we proposed an alternate frequentist adaptive randomization strategy for situations where a large number of biomarkers need to be incorporated in the study design. We also propose a new adaptive randomization rule, which takes into account the variations associated with the point estimates of survival times. In all of our designs, we seek to identify the key markers that are either prognostic or predictive with respect to treatment. We are going to use extensive simulation to evaluate the operating characteristics of our methods.^

Modified 3+3 design for phase I clinical trials

Phase I clinical trial is mainly designed to determine the maximum tolerated dose (MTD) of a new drug. Optimization of phase I trial design is crucial to minimize the number of enrolled patients exposed to unsafe dose levels and to provide reliable information to the later phases of clinical trials. Although it has been criticized about its inefficient MTD estimation, nowadays the traditional 3+3 method remains dominant in practice due to its simplicity and conservative estimation. There are many new designs that have been proven to generate more credible MTD estimation, such as the Continual Reassessment Method (CRM). Despite its accepted better performance, the CRM design is still not widely used in real trials. There are several factors that contribute to the difficulties of CRM adaption in practice. First, CRM is not widely accepted by the regulatory agencies such as FDA in terms of safety. It is considered to be less conservative and tend to expose more patients above the MTD level than the traditional design. Second, CRM is relatively complex and not intuitive for the clinicians to fully understand. Third, the CRM method take much more time and need statistical experts and computer programs throughout the trial. The current situation is that the clinicians still tend to follow the trial process that they are comfortable with. This situation is not likely to change in the near future. Based on this situation, we have the motivation to improve the accuracy of MTD selection while follow the procedure of the traditional design to maintain simplicity. We found that in 3+3 method, the dose transition and the MTD determination are relatively independent. Thus we proposed to separate the two stages. The dose transition rule remained the same as 3+3 method. After getting the toxicity information from the dose transition stage, we combined the isotonic transformation to ensure the monotonic increasing order before selecting the optimal MTD. To compare the operating characteristics of the proposed isotonic method and the other designs, we carried out 10,000 simulation trials under different dose setting scenarios to compare the design characteristics of the isotonic modified method with standard 3+3 method, CRM, biased coin design (BC) and k-in-a-row design (KIAW). The isotonic modified method improved MTD estimation of the standard 3+3 in 39 out of 40 scenarios. The improvement is much greater when the target is 0.3 other than 0.25. The modified design is also competitive when comparing with other selected methods. A CRM method performed better in general but was not as stable as the isotonic method throughout the different dose settings. The results demonstrated that our proposed isotonic modified method is not only easily conducted using the same procedure as 3+3 but also outperforms the conventional 3+3 design. It can also be applied to determine MTD for any given TTL. These features make the isotonic modified method of practical value in phase I clinical trials.^

Complications of misoprostol and other abortion induction methods in the developing world: A systematic review

OBJECTIVE: To systematically review published literature to examine the complications associated with the use of misoprostol and compare these complications to those associated with other forms of abortion induction. ^ DATA SOURCES: Studies were identified through searches of medical literature databases including Medline (Ovid), PubMed (NLM), LILACS, sciELO, and AIM (AFRO), and review of references of relevant articles. ^ STUDY SELECTION AND METHODS: A descriptive systematic review that included studies reported in English and published before December 2012. Eligibility criteria included: misoprostol (with or without other methods) and any other method of abortion in a developing country, as well as quantitative data on the complication of each method. The following is information extracted from each study: author/year, country/city, study design/study sample, age range, setting of data collection, sample size, the method of abortion induction, the number of cases for each method, and the percentage of complications with each method. RESULTS: A total of 4 studies were identified (all in Latin America) describing post-abortion complications of misoprostol and other methods in countries where abortion is generally considered unsafe and/or illegal. The four studies reported on a range of complications including: bleeding, infection, incomplete abortion, intense pelvic pain, uterine perforation, headache, diarrhea, nausea, mechanical lesions, and systemic collapse. The most prevalent complications of misoprostol-induced abortion reported were: bleeding (7-82%), incomplete abortion (33-70%), and infection (0.8-67%). The prevalence of these complications reported from other abortion methods include: bleeding (16-25%), incomplete abortion (15-82%), and infection (13-50%). ^ CONCLUSION: The literature identified by this systematic review is inadequate for determining the complications of misoprostol used in unsafe settings. Abortion is considered an illicit behavior in these countries, therefore making it difficult to investigate the details needed to conduct a study on abortion complications. Given the differences between the reviewed studies as well as a variety of study limitations, it is not possible to draw firm conclusions about the rates of specific-abortion related complications.^