Systems biology for organotypic cell cultures.

Translating in vitro biological data into actionable information related to human health holds the potential to improve disease treatment and risk assessment of chemical exposures. While genomics has identified regulatory pathways at the cellular level, translation to the organism level requires a multiscale approach accounting for intra-cellular regulation, inter-cellular interaction, and tissue/organ-level effects. Tissue-level effects can now be probed in vitro thanks to recently developed systems of three-dimensional (3D), multicellular, "organotypic" cell cultures, which mimic functional responses of living tissue. However, there remains a knowledge gap regarding interactions across different biological scales, complicating accurate prediction of health outcomes from molecular/genomic data and tissue responses. Systems biology aims at mathematical modeling of complex, non-linear biological systems. We propose to apply a systems biology approach to achieve a computational representation of tissue-level physiological responses by integrating empirical data derived from organotypic culture systems with computational models of intracellular pathways to better predict human responses. Successful implementation of this integrated approach will provide a powerful tool for faster, more accurate and cost-effective screening of potential toxicants and therapeutics. On September 11, 2015, an interdisciplinary group of scientists, engineers, and clinicians gathered for a workshop in Research Triangle Park, North Carolina, to discuss this ambitious goal. Participants represented laboratory-based and computational modeling approaches to pharmacology and toxicology, as well as the pharmaceutical industry, government, non-profits, and academia. Discussions focused on identifying critical system perturbations to model, the computational tools required, and the experimental approaches best suited to generating key data.

Sample and data sharing: observations from a central data repository.

OBJECTIVES: From 2003 to 2013, RTI International served as the data repository for the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK). RTI worked closely with two sample repository partners to build and maintain the Central Repository (CR) that made data and samples available to approved requestors. In this paper, we recap aspects of establishing the mechanism; detail the challenges and limitations of data and sample sharing, and explore the future of resource sharing in light of the evolving environment of research funding. DESIGN AND METHODS: Effective maintenance required the system to be flexible and dynamic while at the same time compliant with established data standards. RESULTS: Our years serving as the CR for NIDDK have yielded a number of observations about the difficulties of running a repository, an operation that is by definition dependent on many outside parties whose degree of expertise and efficiency have a direct impact on repository functioning. CONCLUSION: The bio-banking industry will likely continue to become more globally centralized for studying specific genetic diseases and monitoring the health of our environment. The dynamic relationship between emerging technologies and the infrastructure will be needed to support future research that requires the ability of organizations providing support to remain flexible even while following established standards.

'What's in the NIDDK CDR?'--public query tools for the NIDDK central data repository.

The National Institute of Diabetes and Digestive Disease (NIDDK) Central Data Repository (CDR) is a web-enabled resource available to researchers and the general public. The CDR warehouses clinical data and study documentation from NIDDK funded research, including such landmark studies as The Diabetes Control and Complications Trial (DCCT, 1983-93) and the Epidemiology of Diabetes Interventions and Complications (EDIC, 1994-present) follow-up study which has been ongoing for more than 20 years. The CDR also houses data from over 7 million biospecimens representing 2 million subjects. To help users explore the vast amount of data stored in the NIDDK CDR, we developed a suite of search mechanisms called the public query tools (PQTs). Five individual tools are available to search data from multiple perspectives: study search, basic search, ontology search, variable summary and sample by condition. PQT enables users to search for information across studies. Users can search for data such as number of subjects, types of biospecimens and disease outcome variables without prior knowledge of the individual studies. This suite of tools will increase the use and maximize the value of the NIDDK data and biospecimen repositories as important resources for the research community. Database URL: https://www.niddkrepository.org/niddk/home.do.

The NIDDK Central Repository at 8 years--ambition, revision, use and impact.

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Central Repository makes data and biospecimens from NIDDK-funded research available to the broader scientific community. It thereby facilitates: the testing of new hypotheses without new data or biospecimen collection; pooling data across several studies to increase statistical power; and informative genetic analyses using the Repository's well-curated phenotypic data. This article describes the initial database plan for the Repository and its revision using a simpler model. Among the lessons learned were the trade-offs between the complexity of a database design and the costs in time and money of implementation; the importance of integrating consent documents into the basic design; the crucial need for linkage files that associate biospecimen IDs with the masked subject IDs used in deposited data sets; and the importance of standardized procedures to test the integrity data sets prior to distribution. The Repository is currently tracking 111 ongoing NIDDK-funded studies many of which include genotype data, and it houses over 5 million biospecimens of more than 25 types including serum, plasma, stool, urine, DNA, red blood cells, buffy coat and tissue. Repository resources have supported a range of biochemical, clinical, statistical and genetic research (188 external requests for clinical data and 31 for biospecimens have been approved or are pending). Genetic research has included GWAS, validation studies, development of methods to improve statistical power of GWAS and testing of new statistical methods for genetic research. We anticipate that the future impact of the Repository's resources on biomedical research will be enhanced by (i) cross-listing of Repository biospecimens in additional searchable databases and biobank catalogs; (ii) ongoing deployment of new applications for querying the contents of the Repository; and (iii) increased harmonization of procedures, data collection strategies, questionnaires etc. across both research studies and within the vocabularies used by different repositories.

Including the Group Quarters Population in the US Synthesized Population Database.

In 2005, RTI International researchers developed methods to generate synthesized population data on US households for the US Synthesized Population Database. These data are used in agent-based modeling, which simulates large-scale social networks to test how changes in the behaviors of individuals affect the overall network. Group quarters are residences where individuals live in close proximity and interact frequently. Although the Synthesized Population Database represents the population living in households, data for the nation's group quarters residents are not easily quantified because of US Census Bureau reporting methods designed to protect individuals' privacy.Including group quarters population data can be an important factor in agent-based modeling because the number of residents and the frequency of their interactions are variables that directly affect modeling results. Particularly with infectious disease modeling, the increased frequency of agent interaction may increase the probability of infectious disease transmission between individuals and the probability of disease outbreaks.This report reviews our methods to synthesize data on group quarters residents to match US Census Bureau data. Our goal in developing the Group Quarters Population Database was to enable its use with RTI's US Synthesized Population Database in the Modeling of Infectious Diseases Agent Study.

Sharing Research Models: Using Software Engineering Practices for Facilitation.

Increasingly, researchers are turning to computational models to understand the interplay of important variables on systems' behaviors. Although researchers may develop models that meet the needs of their investigation, application limitations-such as nonintuitive user interface features and data input specifications-may limit the sharing of these tools with other research groups. By removing these barriers, other research groups that perform related work can leverage these work products to expedite their own investigations. The use of software engineering practices can enable managed application production and shared research artifacts among multiple research groups by promoting consistent models, reducing redundant effort, encouraging rigorous peer review, and facilitating research collaborations that are supported by a common toolset. This report discusses three established software engineering practices- the iterative software development process, object-oriented methodology, and Unified Modeling Language-and the applicability of these practices to computational model development. Our efforts to modify the MIDAS TranStat application to make it more user-friendly are presented as an example of how computational models that are based on research and developed using software engineering practices can benefit a broader audience of researchers.

The benefits to all of ensuring equal and timely access to influenza vaccines in poor communities.

When influenza vaccines are in short supply, allocating vaccines equitably among different jurisdictions can be challenging. But justice is not the only reason to ensure that poorer counties have the same access to influenza vaccines as do wealthier ones. Using a detailed computer simulation model of the Washington, D.C., metropolitan region, we found that limiting or delaying vaccination of residents of poorer counties could raise the total number of influenza infections and the number of new infections per day at the peak of an epidemic throughout the region-even in the wealthier counties that had received more timely and abundant vaccine access. Among other underlying reasons, poorer counties tend to have high-density populations and more children and other higher-risk people per household, resulting in more interactions and both increased transmission of influenza and greater risk for worse influenza outcomes. Thus, policy makers across the country, in poor and wealthy areas alike, have an incentive to ensure that poorer residents have equal access to vaccines.

Would school closure for the 2009 H1N1 influenza epidemic have been worth the cost?: a computational simulation of Pennsylvania.

BACKGROUND: During the 2009 H1N1 influenza epidemic, policy makers debated over whether, when, and how long to close schools. While closing schools could have reduced influenza transmission thereby preventing cases, deaths, and health care costs, it may also have incurred substantial costs from increased childcare needs and lost productivity by teachers and other school employees. METHODS: A combination of agent-based and Monte Carlo economic simulation modeling was used to determine the cost-benefit of closing schools (vs. not closing schools) for different durations (range: 1 to 8 weeks) and symptomatic case incidence triggers (range: 1 to 30) for the state of Pennsylvania during the 2009 H1N1 epidemic. Different scenarios varied the basic reproductive rate (R(0)) from 1.2, 1.6, to 2.0 and used case-hospitalization and case-fatality rates from the 2009 epidemic. Additional analyses determined the cost per influenza case averted of implementing school closure. RESULTS: For all scenarios explored, closing schools resulted in substantially higher net costs than not closing schools. For R(0) = 1.2, 1.6, and 2.0 epidemics, closing schools for 8 weeks would have resulted in median net costs of $21.0 billion (95% Range: $8.0 - $45.3 billion). The median cost per influenza case averted would have been $14,185 ($5,423 - $30,565) for R(0) = 1.2, $25,253 ($9,501 - $53,461) for R(0) = 1.6, and $23,483 ($8,870 - $50,926) for R(0) = 2.0. CONCLUSIONS: Our study suggests that closing schools during the 2009 H1N1 epidemic could have resulted in substantial costs to society as the potential costs of lost productivity and childcare could have far outweighed the cost savings in preventing influenza cases.

A computer simulation of vaccine prioritization, allocation, and rationing during the 2009 H1N1 influenza pandemic.

In the fall 2009, the University of Pittsburgh Models of Infectious Disease Agent Study (MIDAS) team employed an agent-based computer simulation model (ABM) of the greater Washington, DC, metropolitan region to assist the Office of the Assistant Secretary of Public Preparedness and Response, Department of Health and Human Services, to address several key questions regarding vaccine allocation during the 2009 H1N1 influenza pandemic, including comparing a vaccinating children (i.e., highest transmitters)-first policy versus the Advisory Committee on Immunization Practices (ACIP)-recommended vaccinating at-risk individuals-first policy. Our study supported adherence to the ACIP (instead of a children-first policy) prioritization recommendations for the H1N1 influenza vaccine when vaccine is in limited supply and that within the ACIP groups, children should receive highest priority.

A computer simulation of employee vaccination to mitigate an influenza epidemic.

BACKGROUND: Better understanding the possible effects of vaccinating employees is important and can help policymakers and businesses plan vaccine distribution and administration logistics, especially with the current H1N1 influenza vaccine in short supply. PURPOSE: This article aims to determine the effects of varying vaccine coverage, compliance, administration rates, prioritization, and timing among employees during an influenza pandemic. METHODS: As part of the H1N1 influenza planning efforts of the Models of Infectious Disease Agent Study network, an agent-based computer simulation model was developed for the Washington DC metropolitan region, encompassing five metropolitan statistical areas. Each simulation run involved introducing 100 infectious individuals to initiate a 1.3 reproductive-rate (R(0)) epidemic, consistent with H1N1 parameters to date. Another set of scenarios represented a R(0)=1.6 epidemic. RESULTS: An unmitigated epidemic resulted in substantial productivity losses (a mean of $112.6 million for a serologic 15% attack rate and $193.8 million for a serologic 25% attack rate), even with the relatively low estimated mortality impact of H1N1. Although vaccinating Advisory Committee on Immunization Practices-defined priority groups resulted in the largest savings, vaccinating all remaining workers captured additional savings and, in fact, reduced healthcare workers' and critical infrastructure workers' chances of infection. Moreover, although employee vaccination compliance affected the epidemic, once 20% compliance was achieved, additional increases in compliance provided less incremental benefit. Even though a vast majority of the workplaces in the DC metropolitan region had fewer than 100 employees, focusing on vaccinating only those in larger firms (> or =100 employees) was just as effective in mitigating the epidemic as trying to vaccinate employees in all workplaces. CONCLUSIONS: Timely vaccination of at least 20% of the large-company workforce can play an important role in epidemic mitigation.

Attribute Assignment to a Synthetic Population in Support of Agent-Based Disease Modeling.

Communicable-disease transmission models are useful for the testing of prevention and intervention strategies. Agent-based models (ABMs) represent a new and important class of the many types of disease transmission models in use. Agent-based disease models benefit from their ability to assign disease transmission probabilities based on characteristics shared by individual agents. These shared characteristics allow ABMs to apply transmission probabilities when agents come together in geographic space. Modeling these types of social interactions requires data, and the results of the model largely depend on the quality of these input data. We initially generated a synthetic population for the United States, in support of the Models of Infectious Disease Agent Study. Subsequently, we created shared characteristics to use in ABMs. The specific goals for this task were to assign the appropriately aged populations to schools, workplaces, and public transit. Each goal presented its own challenges and problems; therefore, we used different techniques to create each type of shared characteristic. These shared characteristics have allowed disease models to more realistically predict the spread of disease, both spatially and temporally.

Synthesized Population Databases: A US Geospatial Database for Agent-Based Models.

Agent-based models simulate large-scale social systems. They assign behaviors and activities to "agents" (individuals) within the population being modeled and then allow the agents to interact with the environment and each other in complex simulations. Agent-based models are frequently used to simulate infectious disease outbreaks, among other uses.RTI used and extended an iterative proportional fitting method to generate a synthesized, geospatially explicit, human agent database that represents the US population in the 50 states and the District of Columbia in the year 2000. Each agent is assigned to a household; other agents make up the household occupants.For this database, RTI developed the methods for generating synthesized households and personsassigning agents to schools and workplaces so that complex interactions among agents as they go about their daily activities can be taken into accountgenerating synthesized human agents who occupy group quarters (military bases, college dormitories, prisons, nursing homes).In this report, we describe both the methods used to generate the synthesized population database and the final data structure and data content of the database. This information will provide researchers with the information they need to use the database in developing agent-based models.Portions of the synthesized agent database are available to any user upon request. RTI will extract a portion (a county, region, or state) of the database for users who wish to use this database in their own agent-based models.

NIDDK data repository: a central collection of clinical trial data.

BACKGROUND: The National Institute of Diabetes and Digestive and Kidney Diseases have established central repositories for the collection of DNA, biological samples, and clinical data to be catalogued at a single site. Here we present an overview of the site which stores the clinical data and links to biospecimens. DESCRIPTION: The NIDDK Data repository is a web-enabled resource cataloguing clinical trial data and supporting information from NIDDK supported studies. The Data Repository allows for the co-location of multiple electronic datasets that were created as part of clinical investigations. The Data Repository does not serve the role of a Data Coordinating Center, but rather as a warehouse for the clinical findings once the trials have been completed. Because both biological and genetic samples are collected from many of the studies, a data management system for the cataloguing and retrieval of samples was developed. CONCLUSION: The Data Repository provides a unique resource for researchers in the clinical areas supported by NIDDK. In addition to providing a warehouse of data, Data Repository staff work with the users to educate them on the datasets as well as assist them in the acquisition of multiple data sets for cross-study analysis. Unlike the majority of biological databases, the Data Repository acts both as a catalogue for data, biosamples, and genetic materials and as a central processing point for the requests for all biospecimens. Due to regulations on the use of clinical data, the ultimate release of that data is governed under NIDDK data release policies. The Data Repository serves as the conduit for such requests.

Strategies for mitigating an influenza pandemic.

Development of strategies for mitigating the severity of a new influenza pandemic is now a top global public health priority. Influenza prevention and containment strategies can be considered under the broad categories of antiviral, vaccine and non-pharmaceutical (case isolation, household quarantine, school or workplace closure, restrictions on travel) measures. Mathematical models are powerful tools for exploring this complex landscape of intervention strategies and quantifying the potential costs and benefits of different options. Here we use a large-scale epidemic simulation to examine intervention options should initial containment of a novel influenza outbreak fail, using Great Britain and the United States as examples. We find that border restrictions and/or internal travel restrictions are unlikely to delay spread by more than 2-3 weeks unless more than 99% effective. School closure during the peak of a pandemic can reduce peak attack rates by up to 40%, but has little impact on overall attack rates, whereas case isolation or household quarantine could have a significant impact, if feasible. Treatment of clinical cases can reduce transmission, but only if antivirals are given within a day of symptoms starting. Given enough drugs for 50% of the population, household-based prophylaxis coupled with reactive school closure could reduce clinical attack rates by 40-50%. More widespread prophylaxis would be even more logistically challenging but might reduce attack rates by over 75%. Vaccine stockpiled in advance of a pandemic could significantly reduce attack rates even if of low efficacy. Estimates of policy effectiveness will change if the characteristics of a future pandemic strain differ substantially from those seen in past pandemics.

SAME-GENDER SEX IN THE UNITED STATES IMPACT OF T-ACASI ON PREVALENCE ESTIMATES.

Well-conducted telephone surveys provide an economical means of estimating the prevalence of sexual and reproductive behaviors in a population. There is, however, a nontrivial potential for bias since respondents must report sensitive information to a human interviewer. The National STD and Behavior Measurement Experiment (NSBME) evaluates a new survey technology-telephone audio computer-assisted self-interviewing (T-ACASI)-that eliminates this requirement. The NSBME embedded a randomized experiment in a survey of probability samples of 1,543 U.S. and 744 Baltimore adults ages 18 to 45. Compared with NSBME respondents interviewed by human interviewers, respondents interviewed by T-ACASI were 1.5 to 1.6 times more likely to report same-gender sexual attraction, experience, and genital contact. The impact of T-ACASI was more pronounced (odds ratio = 2.5) for residents of locales that have historically been less tolerant of same-gender sexual behaviors and for respondents in households with children (odds ratio = 3.0).

Using Touch Screen Audio-CASI to Obtain Data on Sensitive Topics.

This paper describes a new interview data collection system that uses a laptop personal computer equipped with a touch-sensitive video monitor. The touch-screen-based audio computer-assisted self-interviewing system, or touch screen audio-CASI, enhances the ease of use of conventional audio CASI systems while simultaneously providing the privacy of self-administered questionnaires. We describe touch screen audio-CASI design features and operational characteristics. In addition, we present data from a recent clinic-based experiment indicating that the touch audio-CASI system is stable, robust, and suitable for administering relatively long and complex questionnaires on sensitive topics, including drug use and sexual behaviors associated with HIV and other sexually transmitted diseases.

Implementing Audio-CASI on Windows' Platforms.

Audio computer-assisted self interviewing (Audio-CASI) technologies have recently been shown to provide important and sometimes dramatic improvements in the quality of survey measurements. This is particularly true for measurements requiring respondents to divulge highly sensitive information such as their sexual, drug use, or other sensitive behaviors. However, DOS-based Audio-CASI systems that were designed and adopted in the early 1990s have important limitations. Most salient is the poor control they provide for manipulating the video presentation of survey questions. This article reports our experiences adapting Audio-CASI to Microsoft Windows 3.1 and Windows 95 platforms. Overall, our Windows-based system provided the desired control over video presentation and afforded other advantages including compatibility with a much wider array of audio devices than our DOS-based Audio-CASI technologies. These advantages came at the cost of increased system requirements --including the need for both more RAM and larger hard disks. While these costs will be an issue for organizations converting large inventories of PCS to Windows Audio-CASI today, this will not be a serious constraint for organizations and individuals with small inventories of machines to upgrade or those purchasing new machines today.

Automating Telephone Surveys: Using T-ACASI to Obtain Data on Sensitive Topics.

This paper describes a new interview data collection system that uses a personal computer equipped with a telephone interface card. This system, telephone audio computer-assisted self-interviewing or T-ACASI, offers the economy of telephone interviews while providing the privacy of self-administered questionnaires. We describe T-ACASI design considerations and operational characteristics. In addition, we present data from recent studies indicating that the T-ACASI system is stable, robust, and suitable for administering relatively long and complex questionnaires on sensitive topics, including drug use and sexual behaviors associated with HIV and other STDs.

AUDIO-CASI: Hardware and Software Considerations in Adding Sound to a Computer-Assisted Interviewing System.

This article reviews a multimedia application in the area of survey measurement research: adding audio capabilities to a computer-assisted interviewing system. Hardware and software issues are discussed, and potential hardware devices that operate from DOS platforms are reviewed. Three types of hardware devices are considered: PCMCIA devices, parallel port attachments, and laptops with built-in sound.