Systems Approaches to Biology and Disease Enable Translational Systems Medicine

The development and application of systems strategies to biology and disease are transforming medical research and clinical practice in an unprecedented rate.In the foreseeable future,clinicians,medical researchers,and ultimately the consumers and patients will be increasingly equipped with a deluge of personal health information,e.g.,whole genome sequences,molecular profiling of diseased tissues,and periodic multi-analyte blood testing of biomarker panels for disease and wellness.The convergence of these practices will enable accurate prediction of disease susceptibility and early diagnosis for actionable preventive schema and personalized treatment regimes tailored to each individual.It will also entail proactive participation from all major stakeholders in the health care system.We are at the dawn of predictive,preventive,personalized,and participatory(P4) medicine,the fully implementation of which requires marrying basic and clinical researches through advanced systems thinking and the employment of high-throughput technologies in genomics,proteomics,nanofluidics,single-cell analysis,and computation strategies in a highly-orchestrated discipline we termed translational systems medicine.     

Deadlock Avoidance for Sequential Resource Allocation Systems: Hard and Easy Cases

Deadlock is a major problem for systems that allocate resources in real time. The key issue in deadlock avoidance is whether or not a given resource allocation state is safe: that is, whether or not there exists a sequence of resource allocations that completes all processes. Although safety is established as NP-complete for certain broad resource allocation classes, newly emerging resource allocation scenarios often exhibit unique features not considered in previous work. In these cases, establishing the underlying complexity of the safety problem is essential for developing the best deadlock avoidance approach. This work investigates the complexity of safe resource allocation for a class of systems relevant in automated manufacturing. For this class, the resource needs of each process are expressed as a well-defined sequence. Each request is for a single unit of a single resource and is accompanied by a promise to release the previously allocated resource. Manufacturing researchers have generally accepted that safety is computationally hard, and numerous suboptimal deadlock avoidance solutions have been proposed for this class. Recent results, however, indicate that safety is often computationally easy. The objective of this article is to settle this question by formally establishing the NP-completeness of safety for this class and investigating the boundary between the hard and easy cases. We discuss several special structures that lead to computationally tractable safety characteristics.     

Rotavirus Surveillance at a WHO-Coordinated Invasive Bacterial Disease Surveillance Site in Bangladesh: A Feasibility Study to Integrate Two Surveillance Systems

The World Health Organization (WHO) currently coordinates rotavirus diarrhea and invasive bacterial disease (IBD) surveillance at 178 sentinel sites in 60 countries. However, only 78 sites participate in both surveillance systems using a common sentinel site. Here, we explored the feasibility of extending a WHO-IBD surveillance platform to generate data on the burden of rotaviral diarrhea and its epidemiological characteristics to prepare the countries to measure the impact of rotaviral vaccine. A six-month (July to December, 2012) surveillance, managed by IBD team, collected stool samples and clinical data from under-five children with acute watery diarrhea at an IBD sentinel site. Samples were tested for rotavirus antigen by ELISA and genotyped by PCR at the regional reference laboratory (RRL). Specimens were collected from 79% (n = 297) of eligible cases (n = 375); 100% of which were tested for rotavirus by ELISA and 54% (159/297) of them were positive. At RRL, all the cases were confirmed by PCR and genotyped (99%; 158/159). The typing results revealed the predominance of G12 (40%; 64/159) genotype, followed by G1 (31%; 50/159) and G9 (19%; 31/159). All in all, this exploratory surveillance collected the desired demographic and epidemiological data and achieved almost all the benchmark indicators of WHO, starting from enrollment number to quality assurance through a number of case detection, collection, and testing of specimens and genotyping of strains at RRL. The success of this WHO-IBD site in achieving these benchmark indicators of WHO can be used by WHO as a proof-of-concept for considering integration of rotavirus surveillance with WHO-IBD platforms, specifically in countries with well performing IBD site and no ongoing rotavirus surveillance.     

A Decentralized Approach to Estimate Activity-Based Costs and Near-Optimal Resource Allocation in Flexible Manufacturing Systems

Flexible manufacturing systems (FMSs) can apply the efficiencies of large-scale production to small batch production. The coordination of FMS activities is a complex task; this paper presents a decentralized pricing mechanism that can be used to estimate the activity–based costs and manage the activities of the FMS efficiently. The pricing mechanism described in this paper does not require systemwide information to compute prices; instead, the pricing mechanism samples and uses the demand information at each CNC machine to compute rental prices at that machine. We derive the theoretical formula for rental prices supporting the optimal performance and propose simulation studies to estimate the rental prices for real-time price changes in a decentralized manner. Results from a preliminary simulation study indicate that stable rental prices can be estimated and significant improvements can be realized by using the pricing mechanism.     

Fair Resource Allocation to Health Research: Priority Topics for Bioethics Scholarship

This article draws attention to the limited amount of scholarship on what constitutes fairness and equity in resource allocation to health research by individual funders. It identifies three key decisions of ethical significance about resource allocation that research funders make regularly and calls for prioritizing scholarship on those topics – namely, how health resources should be fairly apportioned amongst public health and health care delivery versus health research, how health research resources should be fairly allocated between health problems experienced domestically versus other health problems typically experienced by disadvantaged populations outside the funder's country, and how domestic and non‐domestic health research funding should be further apportioned to different areas, e.g. types of research and recipients. These three topics should be priorities for bioethics research because their outcomes have a substantial bearing on the achievement of health justice. The proposed agenda aims to move discussion on the ethics of health research funding beyond its current focus on the mismatch between worldwide basic and clinical research investment and the global burden of disease. Individual funders’ decision‐making on whether and to what extent to allocate resources to non‐domestic health research, health systems research, research on the social determinants of health, capacity development, and recipients in certain countries should also be the focus of ethical scrutiny.     

Methodological Approaches to Evaluate Teratogenic Risk Using Birth Defect Registries: Advantages and Disadvantages

Background

Different approaches have been used in case-control studies to estimate maternal exposure to medications and the risk of birth defects. However, the performance of these approaches and how they affect the odds ratio (OR) estimates have not been evaluated using birth-defect surveillance programmes. The aim of this study was to evaluate the scope and limitations of three case-control approaches to assess the teratogenic risk of birth defects in mothers exposed to antiepileptic medications, insulin, or acetaminophen.

Methodology/Principal Findings

We studied 110,814 non-malformed newborns and 58,514 live newborns with birth defects registered by the Latin American Collaborative Study of Congenital Anomalies (ECLAMC) between 1967 and 2008. Four controls were randomly selected for each case in the same hospital and period, and three different control groups were used: non-malformed newborns (HEALTHY), malformed newborns (SICK), and a subgroup of SICK, only-exposed cases (OECA). Associations were evaluated using OR and Pearson''s chi-square (P<0.01). There were no concordance correlations between the HEALTHY and OECA designs, and the average OR differences ranged from 3.0 to 11.5 for the three evaluated medicines. The overestimations observed for HEALTHY design were increased as higher OR values were given, with a high and statistically significant correlation between the difference and the mean. On the contrary, the concordance correlations obtained between the SICK and OECA designs were quite good, with no significant differences in the average risks.

Conclusions

The HEALTHY design estimates the true population OR, but shows a high rate of false-positive results presumably caused by differential misclassification bias. This bias decreases with the increase of the proportion of exposed controls. SICK and OECA odds ratios cannot be considered a direct estimate of the true population OR except under certain conditions. However, the SICK and OECA designs could provide practical information to generate hypotheses about potential teratogens.     

Neurochemical and Behavioral Characteristics of Toxic Milk Mice: An Animal Model of Wilson’s Disease

Toxic milk mice have an inherited defect of copper metabolism. Hepatic phenotype of the toxic milk mice is similar to clinical findings in humans suffering from Wilson’s disease (WND). In the present study, neurotransmitter system and locomotor performance in toxic milk mice was examined to verify the feasibility of this animal model for studying neuropathology of WND. Mice aged 2 and 12 months were used in the experiment. The mice were tested according to rotarod and footprint protocols. Monoamine content in brain structures was measured by high performance liquid chromatography. In order to detect neuronal loss, expression of enzymes specific for dopaminergic [tyrosine hydroxylase (TH)], noradrenergic (dopamine beta-hydroxylase) and serotoninergic [tryptophan hydroxylase (TPH)] neurons was analyzed by Western blot. The 12-month-old toxic milk mice demonstrated impaired locomotor performance in behavioral tests. Motor deficits were accompanied by increased copper and serotonin content in different brain regions and slight decrease in dopamine concentration in the striatum. The expression of TH, dopamine beta-hydroxylase and TPH in the various brain structures did not differ between toxic milk mice and control animals. Despite differences in brain pathology between humans and rodents, further exploration of neuronal injury in toxic milk mice is warranted to broaden the understanding of neuropathology in WND.     

Analysis of Different Methodological Approaches to Measuring Microtubule Length in the Cytoplasm of Cultured Cells

It is generally assumed that microtubules in tissue culture cells extend from the centrosome to cell periphery, and the length of individual microtubules averages several dozens of microns. However, direct electron-microscopic measurements have cast some doubt on this assumption. In this study, the average length of microtubules in cultured Vero cells was estimated using a combined approach. The length of free cytoplasmic and centrosomal microtubules was determined by means of electron microscopy in serial sections; concurrently, the length of free microtubules in the lamella was measured in preparations stained with tubulin antibodies (an indirect immunofluorescent method), by tracing saltatory particle movements along the microtubules in living cells. According to the data of immunofluorescent microscopy, microtubule length in the lamella averaged 4.57 ± 3.69 m. However, since two or more microtubules can overlap, their length may be slightly overestimated by this method. On the other hand, saltatory movements are easy to monitor and measure fairly accurately, but their range may be shorter than the actual microtubule length because of a limited processiveness of motors (kinesin and dynein). On average, the trajectories of saltatory movements in living cells were 3.85 ± 0.72 m long. At the electron-microscopic level, microtubule length was analyzed using pseudo-three-dimensional reconstructions of the microtubule systems around the centrosome and in the lamella. The length of free microtubules in the lamella reached 18 m, averaging 3.33 ± 2.43 m; the average length of centrosomal microtubules was 1.49 ± 0.82 m. Good correspondence between the data on microtubule length and arrangement obtained by different methods allows the conclusion that most of the free microtubules in Vero cells actually have a length of 2–5 m; i.e., they are much shorter than the cell radius (about 25 m). Microtubules extending from the centrosome are shorter still and do not reach the cell periphery. Thus, most microtubules in the lamella of Vero cells are free and their ordered arrangement is not associated with their attachment to the centrosome.     

Behavioral studies,molecular approaches,and modeling: Methodological contributions to biological control success

Modern biological control practitioners must increasingly demonstrate a level of rigor that can only be achieved through use of effective methodological tools such as modeling, behavioral studies and molecular approaches. The use of these technologies is maturing rapidly in biological control and makes tangible contributions to its success. Behavioral studies often uncover important aspects of biology that would otherwise be overlooked, such as the influence of pre-release handling on establishment success and the response of natural enemies to host-induced plant volatiles. Molecular approaches allow the identification and detection of genetically distinct populations of invasive pest species and their natural enemies, tracing the origin of invasive pest populations and compatible natural enemies, and development of improved recombinant natural enemies. Modeling enables theory and empirical observation to optimize agent selection and release, and to predict quantitative impacts on target and non-target populations. All three methodologies, particularly in combination, contribute to our understanding of the reasons for success and failure in biological control, and together with post-release validation studies build the foundations to improve the success of future biological control releases.     

Approaches for Quantifying the Metabolism of Physical Economies: Part I: Methodological Overview

This article is the first of a two-part series that describes and compares the essential features of nine existing "physical economy" approaches for quantifying the material demands of the human economy upon the natural environment. A range of material flow analysis (MFA) and related techniques is assessed and compared in terms of several major dimensions. These include the system boundary identification for material flow sources, extents, and the key socioinstitutional entities containing relevant driving forces, as well as the nature and detailing of system components and flow interconnections, and the comprehensiveness and types of flows and materials covered.
Shared conceptual themes of a new wave of physical economy approaches are described with a brief overview of the potential applications of this broad family of methodologies. The evolving and somewhat controversial nature of the characteristics and role that define MFA is examined. This review suggests the need to specify whether MFA is a general metabolic flow measurement procedure that can be applied from micro to macrolevels of economic activity, or a more specific methodology aimed primarily at economy-wide analyses that "map" the material relations between society and nature. Some alternative options for classifying MFA are introduced for discussion before a more detailed comparative summary of the key methodological features of each approach in the second part of this two-part article.
The review is presented (1) as a reference and resource for the increasing number of policy makers and practitioners involved in industrial ecology and the evaluation of the material basis of economies and the formulation of eco-efficiency strategies, and (2) to provoke discussion and ongoing dialogue to clarify the many existing areas of discordance in environmental accounting related to material flows, and help consolidate the methodological basis and application of MFA.     

Animal Consciousness: Some Philosophical, Methodological, and Evolutionary Problems

No consensus exists concerning the mechanisms, distribution,or adaptive significance of consciousness. Agreement on anyone of these issues would aid in resolving others. Given a reliablebehavioral or neuroanatomical test for consciousness, we couldmap its distribution and describe its evolution. Conversely,if we knew its distribution, we could assess its adaptive valueand look for similarly distributed neuroanatomies to help usget at its mechanisms. Morgan's Canon—the rule that we should avoid attributinghumanlike mental states to other animals whenever possible—impedesthe use of the comparative method in unraveling this knot. Ifinterpreted in this context as a parsimony criterion, Morgan'sCanon is logically equivalent to epiphenomenalism. It is parsimoniousif and only if conscious mental events play no causal role inhuman behavior and human consciousness has no adaptive significance.Rejecting this conclusion entails rejecting the parsimony interpretationof Morgan's Canon.     

Hospitalization Records as a Tool for Evaluating Performance of Food- and Water-Borne Disease Surveillance Systems: A Massachusetts Case Study

We outline a framework for evaluating food- and water-borne surveillance systems using hospitalization records, and demonstrate the approach using data on salmonellosis, campylobacteriosis and giardiasis in persons aged ≥65 years in Massachusetts. For each infection, and for each reporting jurisdiction, we generated smoothed standardized morbidity ratios (SMR) and surveillance to hospitalization ratios (SHR) by comparing observed surveillance counts with expected values or the number of hospitalized cases, respectively. We examined the spatial distribution of SHR and related this to the mean for the entire state. Through this approach municipalities that deviated from the typical experience were identified and suspected of under-reporting. Regression analysis revealed that SHR was a significant predictor of SMR, after adjusting for population age-structure. This confirms that the spatial “signal” depicted by surveillance is in part influenced by inconsistent testing and reporting practices since municipalities that reported fewer cases relative to the number of hospitalizations had a lower relative risk (as estimated by SMR). Periodic assessment of SHR has potential in assessing the performance of surveillance systems.