GRADE Guidelines 30: the GRADE approach to assessing the certainty of modeled evidence—An overview in the context of health decision-making

Objectives: The objective of the study is to present the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) conceptual approach to the assessment of certainty of evidence from modeling studies (i.e., certainty associated with model outputs). / Study Design and Setting: Expert consultations and an international multidisciplinary workshop informed development of a conceptual approach to assessing the certainty of evidence from models within the context of systematic reviews, health technology assessments, and health care decisions. The discussions also clarified selected concepts and terminology used in the GRADE approach and by the modeling community. Feedback from experts in a broad range of modeling and health care disciplines addressed the content validity of the approach. / Results: Workshop participants agreed that the domains determining the certainty of evidence previously identified in the GRADE approach (risk of bias, indirectness, inconsistency, imprecision, reporting bias, magnitude of an effect, dose–response relation, and the direction of residual confounding) also apply when assessing the certainty of evidence from models. The assessment depends on the nature of model inputs and the model itself and on whether one is evaluating evidence from a single model or multiple models. We propose a framework for selecting the best available evidence from models: 1) developing de novo, a model specific to the situation of interest, 2) identifying an existing model, the outputs of which provide the highest certainty evidence for the situation of interest, either “off-the-shelf” or after adaptation, and 3) using outputs from multiple models. We also present a summary of preferred terminology to facilitate communication among modeling and health care disciplines. / Conclusion: This conceptual GRADE approach provides a framework for using evidence from models in health decision-making and the assessment of certainty of evidence from a model or models. The GRADE Working Group and the modeling community are currently developing the detailed methods and related guidance for assessing specific domains determining the certainty of evidence from models across health care–related disciplines (e.g., therapeutic decision-making, toxicology, environmental health, and health economics)

Evidence for the Complexity of MicroRNA-Mediated Regulation in Ovarian Cancer: A Systems Approach

MicroRNAs (miRNAs) are short (∼22 nucleotides) regulatory RNAs that can modulate gene expression and are aberrantly expressed in many diseases including cancer. Previous studies have shown that miRNAs inhibit the translation and facilitate the degradation of their targeted messenger RNAs (mRNAs) making them attractive candidates for use in cancer therapy. However, the potential clinical utility of miRNAs in cancer therapy rests heavily upon our ability to understand and accurately predict the consequences of fluctuations in levels of miRNAs within the context of complex tumor cells. To evaluate the predictive power of current models, levels of miRNAs and their targeted mRNAs were measured in laser captured micro-dissected (LCM) ovarian cancer epithelial cells (CEPI) and compared with levels present in ovarian surface epithelial cells (OSE). We found that the predicted inverse correlation between changes in levels of miRNAs and levels of their mRNA targets held for only ∼11% of predicted target mRNAs. We demonstrate that this low inverse correlation between changes in levels of miRNAs and their target mRNAs in vivo is not merely an artifact of inaccurate miRNA target predictions but the likely consequence of indirect cellular processes that modulate the regulatory effects of miRNAs in vivo. Our findings underscore the complexities of miRNA-mediated regulation in vivo and the necessity of understanding the basis of these complexities in cancer cells before the therapeutic potential of miRNAs can be fully realized

GRADE Guidelines 30: The GRADE Approach to Assessing the Certainty of Modelled Evidence - an Overview in the Context of Health Decision-making.

OBJECTIVES: To present the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) conceptual approach to the assessment of certainty of evidence from modelling studies (i.e. certainty associated with model outputs). STUDY DESIGN AND SETTING: Expert consultations and, an international multi-disciplinary workshop informed development of a conceptual approach to assessing the certainty of evidence from models within the context of systematic reviews, health technology assessments, and health care decisions. The discussions also clarified selected concepts and terminology used in the GRADE approach and by the modelling community. Feedback from experts in a broad range of modelling and health care disciplines addressed the content validity of the approach. RESULTS: Workshop participants agreed, that the domains determining the certainty of evidence previously identified in the GRADE approach (risk of bias, indirectness, inconsistency, imprecision, reporting bias, magnitude of an effect, dose-response relation, and the direction of residual confounding) also apply when of assessing the certainty of evidence from models. The assessment depends on the nature of model inputs and the model itself and on whether one is evaluating evidence from a single model or multiple models. We propose a framework for selecting the best available evidence from models: 1) developing de novo a model specific to the situation of interest, 2) identifying an existing model the outputs of which provide the highest certainty evidence for the situation of interest, either "off the shelf" or after adaptation, and 3) using outputs from multiple models. We also present a summary of preferred terminology to facilitate communication among modelling and health care disciplines. CONCLUSIONS: This conceptual GRADE approach provides a framework for using evidence from models in health decision making and the assessment of certainty of evidence from a model or models. The GRADE Working Group and the modelling community are currently developing the detailed methods and related guidance for assessing specific domains determining the certainty of evidence from models across health care-related disciplines (e.g. therapeutic decision-making, toxicology, environmental health, health economics)

Cinéma réflexif : une tendance iranienne (Abbas Kiarostami, Mohsen Makhmalbaf et Jafar Panahi)

Starting with Close up (Abbas Kiarostami, 1990), Iranian filmmakers Abbas Kiarostami and Mohsen Makhmalbaf make several films about cinema. Then it's Jafar Panahi, banned from filming, who took an interest in it in his turn. Some of their works are particularly significant and have many similarities with each other. These are Close up (Abbas Kiarostami, 1990), Through the Olive Trees (Abbas Kiarostami, 1994), Salam cinema (Mohsen Makhmalbaf, 1995), This is not a Film (Jafar Panahi, 2011), Taxi Tehran (Jafar Panahi, 2015) and Three Faces (Jafar Panahi, 2017). In trying to define whether it is a question of "reflexive cinema" or "meta-cinema", we realize that there is a rather Western distinction between these often confused notions, whereas we are interested in an Eastern cinematography. We then take the side of reflexivity because its field of application is broader and meta-cinema is more directly critical, which is less conceivable under an Iranian regime that practices censorship. Thus, this thesis intends to confront these films with the different manifestations of reflexivity identified, in order to see to what extent the filmmakers of the films monopolize them, and thus to identify more and more links between these works, in order to legitimize a true Iranian tendency of reflexive cinema. Finally, it is a question of looking at the way in which cinema can be used here to allow Iranian introspection.À partir de Close up (Abbas Kiarostami, 1990), les cinéastes iraniens Abbas Kiarostami et Mohsen Makhmalbaf réalisent plusieurs films qui prennent le cinéma comme sujet. Puis, c’est Jafar Panahi, qui, sous le coup d’une interdiction de filmer, s’y intéresse à son tour. Certaines de ces œuvres sont particulièrement significatives et présentent de nombreuses similitudes entre elles. Il s’agit de Close up (Abbas Kiarostami, 1990), Au travers des oliviers (Abbas Kiarostami, 1994), Salam cinéma (Mohsen Makhmalbaf, 1995), ainsi que Ceci n’est pas un film (Jafar Panahi, 2011), Taxi Téhéran (Jafar Panahi, 2015) et Trois visages (Jafar Panahi, 2017). Cherchant à définir si celles-ci relèvent du « cinéma réflexif » ou du « métacinéma », nous nous rendons compte d’une distinction assez occidentale de ces notions souvent confondues, alors que nous nous intéressons à une cinématographie venue d’Orient. Nous prenons alors le parti de la réflexivité car son champ est plus vaste et que le métacinéma est plus directement critique, ce qui est moins envisageable sous un régime iranien qui pratique la censure. Ainsi, ce mémoire entend confronter ces films à différentes manifestations de la réflexivité recensées, afin de voir dans quelle mesure les cinéastes se les accaparent, et de tisser toujours plus de liens entre ces œuvres, afin de légitimer une « véritable tendance iranienne » en termes de cinéma réflexif. Plus encore, il s’agit de s’intéresser à la manière dont réfléchir le cinéma peut ici permettre une introspection iranienne

Identification of metabolites with anticancer properties by computational metabolomics

©2008 Arakaki et al; licensee BioMed Central Ltd.The electronic version of this article is the complete one and can be found online at: http://www.molecular-cancer.com/content/7/1/57doi:10.1186/1476-4598-7-57Background: Certain endogenous metabolites can influence the rate of cancer cell growth. For example, diacylglycerol, ceramides and sphingosine, NAD+ and arginine exert this effect by acting as signaling molecules, while carrying out other important cellular functions. Metabolites can also be involved in the control of cell proliferation by directly regulating gene expression in ways that are signaling pathway-independent, e.g. by direct activation of transcription factors or by inducing epigenetic processes. The fact that metabolites can affect the cancer process on so many levels suggests that the change in concentration of some metabolites that occurs in cancer cells could have an active role in the progress of the disease. Results: CoMet, a fully automated Computational Metabolomics method to predict changes in metabolite levels in cancer cells compared to normal references has been developed and applied to Jurkat T leukemia cells with the goal of testing the following hypothesis: Up or down regulation in cancer cells of the expression of genes encoding for metabolic enzymes leads to changes in intracellular metabolite concentrations that contribute to disease progression. All nine metabolites predicted to be lowered in Jurkat cells with respect to lymphoblasts that were examined (riboflavin, tryptamine, 3- sulfino-L-alanine, menaquinone, dehydroepiandrosterone, α-hydroxystearic acid, hydroxyacetone, seleno-L-methionine and 5,6-dimethylbenzimidazole), exhibited antiproliferative activity that has not been reported before, while only two (bilirubin and androsterone) of the eleven tested metabolites predicted to be increased or unchanged in Jurkat cells displayed significant antiproliferative activity. Conclusion: These results: a) demonstrate that CoMet is a valuable method to identify potential compounds for experimental validation, b) indicate that cancer cell metabolism may be regulated to reduce the intracellular concentration of certain antiproliferative metabolites, leading to uninhibited cellular growth and c) suggest that many other endogenous metabolites with important roles in carcinogenesis are awaiting discovery

Системный подход и имитационное моделирование

The article deals with a number of provisions of the system approach, which arereflected in the modeling of various technical facilities. System approach allows more fully reflect communication domain modeled system between objects on the one hand, the objects and the environment on the other. This can be solved as a problem of the synthesis of the system and the task of investigating the behavior of the existing system. Almost paradigm systematic approach to modeling systems are used in the technology of object-oriented modeling and software. One of the alternatives to the modern object-oriented technology is an agent-based simulation. The behavior of the system is formed as a result of the interaction of objects – agents are able to cooperate with other agents for the realization ofthe objective function of the system.В статье рассмотрены ряд положений системного подхода, которыенаходят отражение при моделировании различных технических объектов. Системный подход позволяет наиболее полно отразить связи в предметной области моделируемой системы между объектами с одной стороны, объектами и внешней средой с другой. При этом может решаться как задача синтеза системы, так и задача исследования поведения существующей системы. Практически парадигмы системного подхода в моделировании систем находят применение в технологии объектно-ориентированной разработки моделей и программного обеспечения. Одной из современных альтернатив реализации объектно-ориентированной технологии является агентное моделирование. Поведение системы формируется как результат взаимодействие объектов – агентов способных кооперироваться с другими агентами для реализации целевой функции системы

Мультиагентное моделирование в среде NetLogo

This article discusses approaches to computer modeling of complex systems in various subject areas. The modeling of such systems should be implemented using the technology of agents. Each agent has an individual behavior and can cooperate with other agents to perform certain functions of the system. As a tool of agent-based modelling is considered the NetLogo program distributed under the GNU GPL. Provides information about the NetLogo programming language, discusses the paradigm of agent-based modelling in virtual World NetLogo. Provides information about agent simulation of vehicle movement, discusses the interaction between agents on the principle of "predator-prey", provides information about landscape models provide information for modeling the movement of agents in the network. Agent-based model created in Netlogo, can be equipped with an interface for data input and output parameters of the simulated system.В статье рассматриваются подходы к компьютерному моделированию сложных систем в различных предметных областях. Моделирование подобных систем целесообразно выполнять с использованием технологии агентов. Каждый агент обладает индивидуальным поведением и может кооперироваться с другими агентами для выполнения определенных функций системы. В качестве инструментального средства агентного моделирования рассматривается программа NetLogo распространяемая по лицензии GNU GPL. Приводятся сведения о языке программирования NetLogo, обсуждаются парадигмы агентного моделирования в виртуальном Мире NetLogo. Приводятся сведения об агентном моделировании движения транспортных средств, обсуждается взаимодействие между агентами по принципу «хищник-жертва», приводятся сведения о ландшафтных моделях, даются сведения о моделировании движения агентов в сети. Агентная модель, созданная в Netlogo, может оснащаться интерфейсом для ввода исходных данных и вывода параметров моделируемой системы

МЕТОДЫ МОДЕЛИРОВАНИЯ КОМПЬЮТЕРНЫХ СЕТЕЙ

A computer network can be considered as a system of mass service, in which as applications are moved information frames. Receiving the information frame, working station may use the received data for transfer to the end user. The resulting information frame is the same portion of data or signal, which is necessary for the organization distributed computing.The article describes the methods of simulation processes for transfer data in computer networks, methods of traffic analysis computer network and the procedure of selection of the optimal configuration topology computer network for the distributed computing.Considered modeling techniques can be used when building a computer network models using specialized software, or they can be implemented as a program, written in procedural or object-oriented programming language.Компьютерная сеть можно рассматривать как систему массового обслуживания, в которых в качестве приложения перемещаются информационных кадров. Получение информационного кадра, работает станция может использовать полученные данные для передачи конечному пользователю. Полученная информация кадра тот же часть данных или сигнала, что необходимо для организации распределенной статья computing.The описывает методы моделирования процессов переноса данных в компьютерных сетях, методы анализа трафика компьютерной сети, а также порядок отбора из Оптимальная конфигурация компьютера топология сети для распределенных computing.Considered методов моделирования могут быть использованы при создании компьютерной сети модели с помощью специализированного программного обеспечения, или они могут быть реализованы в виде программы, написанной в процедурных или объектно-ориентированном языке программирования