A BAYESIAN APPROACH TO DOSE-RESPONSE ASSESSMENT AND DRUG-DRUG INTERACTION ANALYSIS: APPLICATION TO IN VITRO STUDIES

The considerable search for synergistic agents in cancer research is motivated by the therapeutic benefits achieved by combining anti-cancer agents. Synergistic agents make it possible to reduce dosage while maintaining or enhancing a desired effect. Other favorable outcomes of synergistic agents include reduction in toxicity and minimizing or delaying drug resistance. Dose-response assessment and drug-drug interaction analysis play an important part in the drug discovery process, however analysis are often poorly done. This dissertation is an effort to notably improve dose-response assessment and drug-drug interaction analysis. The most commonly used method in published analysis is the Median-Effect Principle/Combination Index method (Chou and Talalay, 1984). The Median-Effect Principle/Combination Index method leads to inefficiency by ignoring important sources of variation inherent in dose-response data and discarding data points that do not fit the Median-Effect Principle. Previous work has shown that the conventional method yields a high rate of false positives (Boik, Boik, Newman, 2008; Hennessey, Rosner, Bast, Chen, 2010) and, in some cases, low power to detect synergy. There is a great need for improving the current methodology. We developed a Bayesian framework for dose-response modeling and drug-drug interaction analysis. First, we developed a hierarchical meta-regression dose-response model that accounts for various sources of variation and uncertainty and allows one to incorporate knowledge from prior studies into the current analysis, thus offering a more efficient and reliable inference. Second, in the case that parametric dose-response models do not fit the data, we developed a practical and flexible nonparametric regression method for meta-analysis of independently repeated dose-response experiments. Third, and lastly, we developed a method, based on Loewe additivity that allows one to quantitatively assess interaction between two agents combined at a fixed dose ratio. The proposed method makes a comprehensive and honest account of uncertainty within drug interaction assessment. Extensive simulation studies show that the novel methodology improves the screening process of effective/synergistic agents and reduces the incidence of type I error. We consider an ovarian cancer cell line study that investigates the combined effect of DNA methylation inhibitors and histone deacetylation inhibitors in human ovarian cancer cell lines. The hypothesis is that the combination of DNA methylation inhibitors and histone deacetylation inhibitors will enhance antiproliferative activity in human ovarian cancer cell lines compared to treatment with each inhibitor alone. By applying the proposed Bayesian methodology, in vitro synergy was declared for DNA methylation inhibitor, 5-AZA-2'-deoxycytidine combined with one histone deacetylation inhibitor, suberoylanilide hydroxamic acid or trichostatin A in the cell lines HEY and SKOV3. This suggests potential new epigenetic therapies in cell growth inhibition of ovarian cancer cells.

A Model for Family Preservation Case Assessment

The outcomes of family preservation practice have been researched and debated. The effectiveness of family preservation is still inconclusive and many of the findings may only be inferred to specific situations. Few studies have addressed the assessment techniques or outcome factors from a qualitative perspective. This article synthesizes current literature, research and practice, and proposes a practice framework with questioning techniques to assist practitioners in assessing the strengths and characteristics of a family, and making decisions on whether or not familybased services are appropriate for the family. Two actual cases are presented to illustrate how the worker can benefit from having the assessment data derived from this model.

The evolution and assessment of pharmaceutical care: Structure, processes, and outcomes

The evolution of pharmaceutical care is identified through a complete review of the literature published in the American Journal of Health-System Pharmacy, the sole comprehensive publication of institutional pharmacy practice. The evolution is categorized according to characteristics of structure (organizational structure, the role of the pharmacist), process (drug delivery systems, formulary management, acquiring drug products, methods to impact drug therapy decisions), and outcomes (cost of drug delivery, cost of drug acquisition and use, improved safety, improved health outcomes) recorded from the 1950s through the 1990s. While significant progress has been made in implementing basic drug distribution systems, levels of pharmacy involvement with direct patient care is still limited.^ A new practice framework suggests enhanced direct patient care involvement through increase in the efficiency and effectiveness of traditional pharmacy services. Recommendations advance internal and external organizational structure relationships that position pharmacists to fully use their unique skills and knowledge to impact drug therapy decisions and outcomes. Specific strategies facilitate expansion of the breadth and scope of each process component in order to expand the depth of integration of pharmacy and pharmaceutical care within the broad healthcare environment. Economic evaluation methods formally evaluate the impact of both operational and clinical interventions.^ Outcome measurements include specific recommendations and methods to increase efficiency of drug acquisition, emphasizing pharmacists' roles that impact physician prescribing decisions. Effectiveness measures include those that improve safety of drug distribution systems, decrease the potential of adverse drug therapy events, and demonstrate that pharmaceutical care can significantly contribute to improvement in overall health status.^ The implementation of the new framework is modeled on a case study at the M.D. Anderson Cancer Center. The implementation of several new drug distribution methods facilitated the redeployment of personnel from distributive functions to direct patient care activities with significant personnel and drug cost reduction. A cost-benefit analysis illustrates that framework process enhancements produced a benefit-to-cost ratio of 7.9. In addition, measures of effectiveness demonstrated significant levels of safety and enhanced drug therapy outcomes. ^

Assessment of Skill and Portability in Regional Marine Biogeochemical Models: Role of Multiple Planktonic Groups

Application of biogeochemical models to the study of marine ecosystems is pervasive, yet objective quantification of these models' performance is rare. Here, 12 lower trophic level models of varying complexity are objectively assessed in two distinct regions (equatorial Pacific and Arabian Sea). Each model was run within an identical one-dimensional physical framework. A consistent variational adjoint implementation assimilating chlorophyll-a, nitrate, export, and primary productivity was applied and the same metrics were used to assess model skill. Experiments were performed in which data were assimilated from each site individually and from both sites simultaneously. A cross-validation experiment was also conducted whereby data were assimilated from one site and the resulting optimal parameters were used to generate a simulation for the second site. When a single pelagic regime is considered, the simplest models fit the data as well as those with multiple phytoplankton functional groups. However, those with multiple phytoplankton functional groups produced lower misfits when the models are required to simulate both regimes using identical parameter values. The cross-validation experiments revealed that as long as only a few key biogeochemical parameters were optimized, the models with greater phytoplankton complexity were generally more portable. Furthermore, models with multiple zooplankton compartments did not necessarily outperform models with single zooplankton compartments, even when zooplankton biomass data are assimilated. Finally, even when different models produced similar least squares model-data misfits, they often did so via very different element flow pathways, highlighting the need for more comprehensive data sets that uniquely constrain these pathways.

Loss estimation for landslides in mountain areas – An integrated toolbox for vulnerability assessment and damage documentation

Global environmental change includes changes in a wide range of global scale phenomena, which are expected to affect a number of physical processes, as well as the vulnerability of the communities that will experience their impact. Decision-makers are in need of tools that will enable them to assess the loss of such processes under different future scenarios and to design risk reduction strategies. In this paper, a tool is presented that can be used by a range of end-users (e.g. local authorities, decision makers, etc.) for the assessment of the monetary loss from future landslide events, with a particular focus on torrential processes. The toolbox includes three functions: a) enhancement of the post-event damage data collection process, b) assessment of monetary loss of future events and c) continuous updating and improvement of an existing vulnerability curve by adding data of recent events. All functions of the tool are demonstrated through examples of its application.

Image-based biomechanical assessment of vertebral body and intervertebral disc in the human lumbar spine

Life expectancy continuously increases but our society faces age-related conditions. Among musculoskeletal diseases, osteoporosis associated with risk of vertebral fracture and degenerative intervertebral disc (IVD) are painful pathologies responsible for tremendous healthcare costs. Hence, reliable diagnostic tools are necessary to plan a treatment or follow up its efficacy. Yet, radiographic and MRI techniques, respectively clinical standards for evaluation of bone strength and IVD degeneration, are unspecific and not objective. Increasingly used in biomedical engineering, CT-based finite element (FE) models constitute the state-of-art for vertebral strength prediction. However, as non-invasive biomechanical evaluation and personalised FE models of the IVD are not available, rigid boundary conditions (BCs) are applied on the FE models to avoid uncertainties of disc degeneration that might bias the predictions. Moreover, considering the impact of low back pain, the biomechanical status of the IVD is needed as a criterion for early disc degeneration. Thus, the first FE study focuses on two rigid BCs applied on the vertebral bodies during compression test of cadaver vertebral bodies, vertebral sections and PMMA embedding. The second FE study highlights the large influence of the intervertebral disc’s compliance on the vertebral strength, damage distribution and its initiation. The third study introduces a new protocol for normalisation of the IVD stiffness in compression, torsion and bending using MRI-based data to account for its morphology. In the last study, a new criterion (Otsu threshold) for disc degeneration based on quantitative MRI data (axial T2 map) is proposed. The results show that vertebral strength and damage distribution computed with rigid BCs are identical. Yet, large discrepancies in strength and damage localisation were observed when the vertebral bodies were loaded via IVDs. The normalisation protocol attenuated the effect of geometry on the IVD stiffnesses without complete suppression. Finally, the Otsu threshold computed in the posterior part of annulus fibrosus was related to the disc biomechanics and meet objectivity and simplicity required for a clinical application. In conclusion, the stiffness normalisation protocol necessary for consistent IVD comparisons and the relation found between degeneration, mechanical response of the IVD and Otsu threshold lead the way for non-invasive evaluation biomechanical status of the IVD. As the FE prediction of vertebral strength is largely influenced by the IVD conditions, this data could also improve the future FE models of osteoporotic vertebra.

Formatives Selbst- und Peer-Assessment im Unterricht peripher venöser Venenpunktion

Das Lernen einer Fertigkeit durch Demonstration und anschließendes Üben wird „Modeling“ genannt. Es basiert darauf, die Diskrepanz zwischen dem Soll-Zustand (Demonstration) und dem Ist-Zustand (Üben) zu erkennen und zu beheben. Dafür ist die exakte Analyse der eigenen Fertigkeiten beim Üben unentbehrlich. Entsprechend ist auch bekannt, dass formative Evaluationen wesentlich zum erfolgreichen Lernen beitragen. Wir haben deshalb im Kurs für periphere Venenpunktion im 3. Studienjahr formatives Selbst- und Peer-Assessment eingeführt. Die Struktur des Assessment entspricht einem DOPS (dircect observation of procedural skills). DOPS stammt aus dem Arbeitsplatz-basieren Assessment und beinhaltet die Beurteilung folgender Kriterien: Vorbereitung/Nachsorge, technische Fertigkeit, Asepsis/Sicherheit, klinische Urteilsfähigkeit, Organisation/Effizienz, professionelles Verhalten, Gesamteindruck. Diese Kriterien wurden für den Unterricht konkretisiert (z.B. Vorbereitung mit Beschriftung der Röhrchen, etc.) und den Studierenden als Merkblätter ausgeteilt. Die Studierenden beurteilten ihre eigene Performance bzw. die eines Kommilitonen, gaben sich Feedback und legten individuelle Lernziele zur Verbesserung fest. Dieses Vorgehen hat den Vorteil, dass sowohl der Übende, als auch der beobachtende Kommilitone, die optimale Ausführung der jeweiligen Tätigkeit reflektieren, welches für beide eine Möglichkeit zum Lernen bietet . Bei der Evaluation des Kurses wurden die Handouts mit den Kriterien der DOPS von Teilnehmern von 9 der 10 Gruppen positiv erwähnt. Im Rahmen eines Debriefing mit den studentischen Tutoren wurde jedoch kritisch angemerkt, dass der Prozess der formativen Selbst- und Fremdevaluation den Studierenden im 3. Studienjahr nicht vertraut war. Es war für die Teilnehmer schwierig konkretes Feedback zu geben und individuelle Lernziele festzulegen. Für das kommende Jahr planen wir in Bezug auf den Kurs folgendes: Die Kriterien der korrekten Durchführung einer Fertigkeit zu formulieren wird von den Teilnehmern als hilfreich empfunden und soll deshalb beibehalten werden. Die Studierenden, die dieses Jahr an dem Kurs teilnehmen, haben bereits ein Feedbacktraining absolviert. Der Kurs kann deshalb neu an Vorkenntnisse anknüpfen. Darüber hinaus soll der Prozess der Festlegung der individuellen Lernziele in der Schulung der studentischen Tutoren des Kurses mehr Gewicht erhalten, damit die Tutoren die Teilnehmer hier gezielt unterstützen können.

Management of Joint Research Activities within ERA-ARD: Guidelines for ARD programme planning, monitoring, evaluation and impact assessment

The present document has been elaborated in the context of the ERA-ARD project “The Agricultural Research for Development (ARD) dimension of the European Research Area (ERA) “. It is based on work done within Task 3.2 to identify a set of common or compatible methodologies for ARD planning, monitoring and evaluation and impact assessment. This set should serve as a guide for the management of joint ARD activities that are presently developed within the framework of the ERA-ARD project.

Sustainable Development Appraisal (SDA): A methodological tool for the participatory assessment of sustainability from local to regional planning levels

The term 'sustainable development' is receiving increasing attention in development co-operation and at the global level. However, practical tools which can help local users and multi-disciplinary teams to work together and apply this general concept at the local to regional levels have' emerged only very recently. This paper describes a tool called 'Sustainable Development Appraisal' (SDA), which is based on the principles of sustainable development, and can be applied by small interdisciplinary teams using a transdisciplinary approach, i.e. in participation with local land users and other stakeholders at various levels of intervention. The SDA has been applied in different parts of the globe. It is receiving considerable attention, and may fulfil most requirements contained in the concept of sustainable development, and yet be practically applicable and useful in the local to regional context. Examples from Eritrea and Ethiopia are used in this paper 'to illustrate the practicability of SDA for development planning and implementation.

A Case Study on Using the Via Christi Breastfeeding Assessment Tool in a Clinical Setting

Aims- The goal of this study is to obtain a subjective point of view of the use, benefits, and shortcomings of the Via Christi breastfeeding Assessment Tool in a clinical setting. Methods- This case study is based on a single yet detailed interview with a lactation consultant who has utilized the Via Christi Breastfeeding Tool in a clinical setting. Findings- Advantages of the Via Christi Breastfeeding Assessment Tool include that the tool is practical and concrete, encompassing both a subjective dimension and the basic elements of breastfeeding. Shortcomings of the tool include its non-specificity in focus on the feeding technique only and excluding other factors involved with the birth and mother- baby couplet. Conclusion- The Via Christi Breastfeeding Tool serves as a good initial screening of breastfeeding, which in result leads to the recommendation of further and more extensive study of a specific mother-baby couplet breastfeeding measures if needed.

A qualitative assessment of multi-level nutrition strategies for reducing racial and ethnic disparities in diabetes

The purpose of this study is to examine the stages of program realization of the interventions that the Bronx Health REACH program initiated at various levels to improve nutrition as a means for reducing racial and ethnic disparities in diabetes. This study was based on secondary analyses of qualitative data collected through the Bronx Health REACH Nutrition Project, a project conducted under the auspices of the Institute on Urban Family Health, with support from the Centers for Disease Control and Prevention (CDC). Local human subjects' review and approval through the Institute on Urban Family Health was required and obtained in order to conduct the Bronx Health REACH Nutrition Project. ^ The study drew from two theoretical models—Glanz and colleagues' nutrition environments model and Shediac-Rizkallah and Bone's sustainability model. The specific study objectives were two-fold: (1) to categorize each nutrition activity to a specific dimension (i.e. consumer, organizational or community nutrition environment); and (2) to evaluate the stage at which the program has been realized (i.e. development, implementation or sustainability). ^ A case study approach was applied and a constant comparative method was used to analyze the data. Triangulation of data based was also conducted. Qualitative data from this study revealed the following principal findings: (1) communities of color are disproportionately experiencing numerous individual and environmental factors contributing to the disparities in diabetes; (2) multi-level strategies that targeted the individual, organizational and community nutrition environments can appropriately address these contributing factors; (3) the nutrition strategies greatly varied in their ability to appropriately meet criteria for the three program stages; and (4) those nutrition strategies most likely to succeed (a) conveyed consistent and culturally relevant messages, (b) had continued involvement from program staff and partners, (c) were able to adapt over time or setting, (d) had a program champion and a training component, (e) were integrated into partnering organizations, and (f) were perceived to be successful by program staff and partners in their efforts to create individual, organizational and community/policy change. As a result of the criteria-based assessment and qualitative findings, an ecological framework elaborating on Glanz and colleagues model was developed. The qualitative findings and the resulting ecological framework developed from this study will help public health professionals and community leaders to develop and implement sustainable multi-level nutrition strategies for addressing racial and ethnic disparities in diabetes. ^

The application of latent variable models to the assessment of determinants of HIV risk behavior

Studies on the relationship between psychosocial determinants and HIV risk behaviors have produced little evidence to support hypotheses based on theoretical relationships. One limitation inherent in many articles in the literature is the method of measurement of the determinants and the analytic approach selected. ^ To reduce the misclassification associated with unit scaling of measures specific to internalized homonegativity, I evaluated the psychometric properties of the Reactions to Homosexuality scale in a confirmatory factor analytic framework. In addition, I assessed the measurement invariance of the scale across racial/ethnic classifications in a sample of men who have sex with men. The resulting measure contained eight items loading on three first-order factors. Invariance assessment identified metric and partial strong invariance between racial/ethnic groups in the sample. ^ Application of the updated measure to a structural model allowed for the exploration of direct and indirect effects of internalized homonegativity on unprotected anal intercourse. Pathways identified in the model show that drug and alcohol use at last sexual encounter, the number of sexual partners in the previous three months and sexual compulsivity all contribute directly to risk behavior. Internalized homonegativity reduced the likelihood of exposure to drugs, alcohol or higher numbers of partners. For men who developed compulsive sexual behavior as a coping strategy for internalized homonegativity, there was an increase in the prevalence odds of risk behavior. ^ In the final stage of the analysis, I conducted a latent profile analysis of the items in the updated Reactions to Homosexuality scale. This analysis identified five distinct profiles, which suggested that the construct was not homogeneous in samples of men who have sex with men. Lack of prior consideration of these distinct manifestations of internalized homonegativity may have contributed to the analytic difficulty in identifying a relationship between the trait and high-risk sexual practices. ^

A qualitative and quantitative assessment of cancer patients' perceptions of barriers to treatment

This study examined barriers that cancer patients experience in obtaining treatment. The principal aim of the study was to conduct a comprehensive quantitative and qualitative assessment of barriers to cancer treatment for Texas cancer patients. The three specific aims of the study were to: (1) conduct a review and critique of published and unpublished research on barriers to cancer treatment; (2) conduct focus groups for the qualitative assessment of cancer patients' perceived barriers to cancer treatment; and (3) survey a representative sample of cancer patients regarding perceived barriers to treatment. The study was guided by the Aday and Andersen access framework of predisposing, enabling, and need determinants of care-seeking.^ To address the first specific aim, a total of 732 abstracts were examined, from which 154 articles were selected for review. Of these 154 articles, 57 that related directly to research on barriers to cancer treatment were chosen for subsequent analysis. Criteria were applied to each article to evaluate the strength of the study design, sampling and measurement procedures. The major barriers that were consistently documented to influence whether or not cancer patients sought or continued required treatment included problems with communication between the patient and provider, lack of information on side effects, the cost of treatment and associated difficulties in obtaining and maintaining insurance coverage, and the absence of formal and informal networks of social support. Access barriers were generally greater for older, minority women, and patients of lower socioeconomic status.^ To address the second specific aim, a total of eight focus groups (n = 44) were conducted across the State of Texas with cancer patients identified by the Texas Community Oncology Network, American Cancer Society, and community health centers. One important finding was that cost is the greatest hurdle that patients face. Another finding was that with the health care/insurance crisis, an increasing number of physicians are working with their patients to develop individually-tailored payment plans. For people in rural areas, travel to treatment sites is a major barrier due to the travel costs as well as work time forfeited by patients and their family members. A third major finding was the patients' family and church play important roles in providing social and emotional support for cancer patients.^ To address the third aim, a total of 910 cancer patients were surveyed during October and November, 1993. Approximately 65% of the cancer patients responded to the survey. The findings showed that the major barriers to treatment included costs of medications and diagnostic tests, transportation, lack of social support, problems understanding the written information regarding their disease as well as losing coverage or having higher premiums or copayments once they were diagnosed (particularly among blacks).^ Significant differences in reported barriers were found between racial groups. The minority respondents (i.e., blacks and Hispanics) tended to experience more barriers to treatment compared to the white respondents. More specifically, Hispanics were more likely to report transportation as a barrier to treatment than both white and blacks. Future research is needed to better understand the problems that minority cancer patients experience in receiving treatment. (Abstract shortened by UMI.) ^

A STUDY TO INVESTIGATE DIET DIVERSITY AS A NUTRITION ASSESSMENT INSTRUMENT

Nutrient intake and specific food item data from 24-hour dietary recalls were utilized to study the relationship between measures of diet diversity and dietary adequacy in a population of white females of child-bearing age and socioeconomic subgroups of that population. As the basis of the diet diversity measures, twelve food groups were constructed from the 24-hour recall data and the number of unique foods per food group counted and weighted according to specified weighting schemes. Utilizing these food groups, nine diet diversity indices were developed.^ Sensitivity/specificity analysis was used to determine the ability of varying levels of selected diet diversity indices to identify individuals above and below preselected intakes of different nutrients. The true prevalence proportions, sensitivity and specificity, false positive and false negative rates, and positive predictive values observed at the selected levels of diet diversity indices were investigated in relation to the objectives and resources of a variety of nutrition improvement programs. Diet diversity indices constructed from the total population data were evaluated as screening tools for respondent nutrient intakes in each of the socioeconomic subgroups as well.^ The results of the sensitivity/specificity analysis demonstrated that the false positive rate, the false negative rate, or both were too high at each diversity cut-off level to validate the widespread use of any of the diversity indices in the dietary assessment of the study population. Although diet diversity has been shown to be highly correlated with the intakes of a number of nutrients, the diet diversity indices constructed in this study did not adequately represent nutrient intakes in the diet as reported, in this study, intakes as reported in the 24-hour dietary recall. Specific cut-off levels of selected diversity indices might have limited application in some nutrition programs. The results were applicable to the sensitivity/specificity analyses in the socioeconomic subgroups as well as in the total population. ^

AN ASSESSMENT OF AFLATOXIN B1, AND OTHER SELECTED VARIABLES, IN A RURAL ENVIRONMENT AND ASSOCIATED CANCER RISK (TEXAS)

A study to assess possible exposure to carcinogenic metabolites (aflatoxins) from a mold Aspergillus flavus has been made in a rice producing area of Brazoria County, Texas. One hundred samples of unmilled rice were analyzed by thin-layer chromatography (TLC) for the amount of aflatoxin produced by the mold during rice growth and storage. Two well water samples and two rice elevator dust samples were also checked for possible aflatoxin content. The mortality rates from gastrointestinal and urinary tract cancers in the rice-growing part of the county were compared with mortality rates in the nonrice-producing areas of the same county.^ This study was an outgrowth of an earlier investigation by Cech and co-workers in Brazoria County which focused on environmental differences, specifically on the quality of drinking water in the former residences of decedents from primary liver cancer. It also compared subjects who died from other causes. The author of this dissertation participated in this phase of the overall investigation by performing some of the chemical analyses and by preparing synographic maps of water quality, and thus, part of those results from the early phase is also included in this manuscript.^ No aflatoxin was detected by TLC methods. However, when extracts of rice dust were checked for mutagenesis by the Ames Salmonella-microsome assay as a supplement to the TLC analysis, the result suggested that these dusts might have contained mutagenic material. The age-adjusted mortality rates in the rice-growing area were higher than those in the comparison area for both male and female gastrointestinal tract cancer and for male urinary tract cancer, but the differences were not statistically significant. ^