Agent-based modeling: a systematic assessment of use cases and requirements for enhancing pharmaceutical research and development productivity.

A crisis continues to brew within the pharmaceutical research and development (R&D) enterprise: productivity continues declining as costs rise, despite ongoing, often dramatic scientific and technical advances. To reverse this trend, we offer various suggestions for both the expansion and broader adoption of modeling and simulation (M&S) methods. We suggest strategies and scenarios intended to enable new M&S use cases that directly engage R&D knowledge generation and build actionable mechanistic insight, thereby opening the door to enhanced productivity. What M&S requirements must be satisfied to access and open the door, and begin reversing the productivity decline? Can current methods and tools fulfill the requirements, or are new methods necessary? We draw on the relevant, recent literature to provide and explore answers. In so doing, we identify essential, key roles for agent-based and other methods. We assemble a list of requirements necessary for M&S to meet the diverse needs distilled from a collection of research, review, and opinion articles. We argue that to realize its full potential, M&S should be actualized within a larger information technology framework--a dynamic knowledge repository--wherein models of various types execute, evolve, and increase in accuracy over time. We offer some details of the issues that must be addressed for such a repository to accrue the capabilities needed to reverse the productivity decline

Increased numbers of neurons occur in the inferior colliculus of the young genetically epilepsy-prone rat

To determine if the increase in the number of neurons observed in the inferior colliculus (IC) of the adult genetically epilepsy-prone rat (GEPR) as compared to the Sprague-Dawley rat was present in the young GEPRs prior to the time at which seizure activity commences, brains from both types of rats 4-10 days of age were studied. A statistically significant increase in the numbers of small neurons occurred in the IC of the young GEPR. At 4 days of age, a 55% increase in the number of small neurons was found in the GEPR as compared to the Sprague-Dawley rat and at 10 days of age this increase was 105%. The numbers of the medium and large neurons were similar in the older group of rats. These data suggest that the increase in cell number observed in the adult GEPR is not compensatory to the seizure activity, but is genetically programmed. © 1985

Anatomical and behavioral analyses of the inheritance of audiogenic seizures in the progeny of genetically epilepsy-prone and Sprague-Dawley rats.

Our previous studies have shown an increase in the number of GABAergic and total neurons in the inferior colliculus (IC) of the genetically epilepsy-prone rat (GEPR-9) as compared to the non-seizing Sprague-Dawley (SD) rat. To determine whether an increase in neuron number in the IC is genetically associated with seizure behavior, seizing and non-seizing offspring of GEPR-9 and SD progenitor strains were studied as well as offspring from backcrosses made with F1 and either GEPR-9 or SD rats. In addition, the ontogeny of seizure behavior was studied in seizing rats from these same backgrounds. The development of seizure behavior in GEPR-9s was shown to be dependent on age and the number of exposures to sound stimulus up until the age of 9 weeks. The F1 and F2 generations displayed different audiogenic seizure profiles than those of the two progenitor strains. In the F1 generation, the ratio of seizing to non-seizing rats was always greater than 3:1, and the distribution of seizure scores was similar for males and females. In addition, the off-spring from backcrosses made with F1 rats (high or low seizing) and GEPR-9s displayed maximal audiogenic response scores (ARS) of 9, a characteristic of the GEPR-9s used in this study. The results of these genetic studies indicate a polygenetic inheritance of this autosomal dominant trait of audiogenic seizure susceptibility. For the quantitative study of neuronal density in the IC, neurons were counted from cresyl violet-stained preparations from seizing and non-seizing F1 and F2 rats, backcrosses from different categories and age-matched SD rats. Statistically significant increases in the number of both small (70% increase) and medium-sized (14% increase) neurons occurred in the high seizing animals (ARS = 7-9) as compared to either the non-seizing F2 or SD rats. In addition, a significant increase in the number of small neurons (77% increase) occurred in the high seizing offspring of the F1 X GEPR-9 backcross as compared to that of the non-seizing offspring of the F1 X SD backcross. The data from 25 rats generated a 0.9 coefficient of linear correlation between ARS and the number of small neurons. The results from the anatomical studies suggest that the inheritance of audiogenic seizures appears to be closely linked to the increase in cell number. Therefore, the increase in cell number in the IC may be an important determinant of seizure behavior for GEPR-9s

Beyond good intentions: lessons on equipment donation from an African hospital.

OBJECTIVE: In 2000, a referral hospital in the Gambia accepted a donation of oxygen concentrators to help maintain oxygen supplies. The concentrators broke down and were put into storage. A case study was done to find the reasons for the problem and to draw lessons to help improve both oxygen supplies and the success of future equipment donations. METHODS: A technical assessment of the concentrators was carried out by a biomedical engineer with relevant expertise. Semi-structured interviews were undertaken with key informants, and content analysis and inductive approaches were applied to construct the history of the episode and the reasons for the failure. FINDINGS: Interviews confirmed the importance of technical problems with the equipment. They also revealed that the donation process was flawed, and that the hospital did not have the expertise to assess or maintain the equipment. Technical assessment showed that all units had the wrong voltage and frequency, leading to overheating and breakdown. Subsequently a hospital donations committee was established to oversee the donations process. On-site biomedical engineering expertise was arranged with a nongovernmental organization (NGO) partner. CONCLUSION: Appropriate donations of medical equipment, including oxygen concentrators, can be of benefit to hospitals in resource-poor settings, but recipients and donors need to actively manage donations to ensure that the donations are beneficial. Success requires planning, technical expertise and local participation. Partners with relevant skills and resources may also be needed. In 2002, WHO produced guidelines for medical equipment donations, which address problems that might be encountered. These guidelines should be publicized and used

Generalized Bayesian Record Linkage and Regression with Exact Error Propagation

Record linkage (de-duplication or entity resolution) is the process of merging noisy databases to remove duplicate entities. While record linkage removes duplicate entities from such databases, the downstream task is any inferential, predictive, or post-linkage task on the linked data. One goal of the downstream task is obtaining a larger reference data set, allowing one to perform more accurate statistical analyses. In addition, there is inherent record linkage uncertainty passed to the downstream task. Motivated by the above, we propose a generalized Bayesian record linkage method and consider multiple regression analysis as the downstream task. Records are linked via a random partition model, which allows for a wide class to be considered. In addition, we jointly model the record linkage and downstream task, which allows one to account for the record linkage uncertainty exactly. Moreover, one is able to generate a feedback propagation mechanism of the information from the proposed Bayesian record linkage model into the downstream task. This feedback effect is essential to eliminate potential biases that can jeopardize resulting downstream task. We apply our methodology to multiple linear regression, and illustrate empirically that the "feedback effect" is able to improve the performance of record linkage.Comment: 18 pages, 5 figure

Preventive measures in infancy to reduce under-five mortality: a case-control study in The Gambia.

OBJECTIVE: To investigate the relationship between child mortality and common preventive interventions: vaccination, trained birthing attendants, tetanus toxoid during pregnancy, breastfeeding and vitamin A supplementation. METHODS: Case-control study in a population under demographic surveillance. Cases (n = 141) were children under five who died. Each was age and sex-matched to five controls (n = 705). Information was gathered by interviewing primary caregivers. RESULTS: All but one of the interventions - whether the mother had received tetanus toxoid during pregnancy - were protective against child mortality after multivariate analysis. Having a trained person assisting at child birth (OR 0.2 95% CI 0.1-0.4), receiving all vaccinations by 9 months of age (OR 0.1; 95% CI 0.01-0.3), being breastfed for more than 12 months (Children breastfed between 13 and 24 months OR 0.1 95% CI 0.03-0.3, more than 25 months OR 0.1 95% CI 0.01-0.5) and receiving vitamin A supplementation at or after 6 months of age (OR 0.05; 95% CI 0.01-0.2) were protective against child death. CONCLUSIONS: This study confirms the value of at least four available interventions in the prevention of under-five death in The Gambia. It is now important to identify those who are not receiving them and why, and to intervene to improve coverage across the population

High Fidelity Tape Transfer Printing Based On Chemically Induced Adhesive Strength Modulation

Transfer printing, a two-step process (i.e. picking up and printing) for heterogeneous integration, has been widely exploited for the fabrication of functional electronics system. To ensure a reliable process, strong adhesion for picking up and weak or no adhesion for printing are required. However, it is challenging to meet the requirements of switchable stamp adhesion. Here we introduce a simple, high fidelity process, namely tape transfer printing(TTP), enabled by chemically induced dramatic modulation in tape adhesive strength. We describe the working mechanism of the adhesion modulation that governs this process and demonstrate the method by high fidelity tape transfer printing several types of materials and devices, including Si pellets arrays, photodetector arrays, and electromyography (EMG) sensors, from their preparation substrates to various alien substrates. High fidelity tape transfer printing of components onto curvilinear surfaces is also illustrated