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      Application of Bayesian evidence synthesis to modelling the effect of ketogenic therapy on survival of high grade glioma patients

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          Abstract

          Background

          Ketogenic therapy in the form of ketogenic diets or calorie restriction has been proposed as a metabolic treatment of high grade glioma (HGG) brain tumors based on mechanistic reasoning obtained mainly from animal experiments. Given the paucity of clinical studies of this relatively new approach, our goal is to extrapolate evidence from the greater number of animal studies and synthesize it with the available human data in order to estimate the expected effects of ketogenic therapy on survival in HGG patients. At the same time we are using this analysis as an example for demonstrating how Bayesianism can be applied in the spirit of a circular view of evidence.

          Results

          A Bayesian hierarchical model was developed. Data from three human cohort studies and 17 animal experiments were included to estimate the effects of four ketogenic interventions (calorie restriction/ketogenic diets as monotherapy/combination therapy) on the restricted mean survival time ratio in humans using various assumptions for the relationships between humans, rats and mice. The impact of different biological assumptions about the relevance of animal data for humans as well as external information based on mechanistic reasoning or case studies was evaluated by specifying appropriate priors. We provide statistical and philosophical arguments for why our approach is an improvement over existing (frequentist) methods for evidence synthesis as it is able to utilize evidence from a variety of sources. Depending on the prior assumptions, a 30–70% restricted mean survival time prolongation in HGG patients was predicted by the models. The highest probability of a benefit (> 90%) for all four ketogenic interventions was obtained when adopting an enthusiastic prior based on previous case reports together with assuming synergism between ketogenic therapies with other forms of treatment. Combinations with other treatments were generally found more effective than ketogenic monotherapy.

          Conclusions

          Combining evidence from both human and animal studies is statistically possible using a Bayesian approach. We found an overall survival-prolonging effect of ketogenic therapy in HGG patients. Our approach is best compatible with a circular instead of hierarchical view of evidence and easy to update once more data become available.

          Electronic supplementary material

          The online version of this article (10.1186/s12976-018-0084-y) contains supplementary material, which is available to authorized users.

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          Most cited references62

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          Toward evidence-based medical statistics. 1: The P value fallacy.

          An important problem exists in the interpretation of modern medical research data: Biological understanding and previous research play little formal role in the interpretation of quantitative results. This phenomenon is manifest in the discussion sections of research articles and ultimately can affect the reliability of conclusions. The standard statistical approach has created this situation by promoting the illusion that conclusions can be produced with certain "error rates," without consideration of information from outside the experiment. This statistical approach, the key components of which are P values and hypothesis tests, is widely perceived as a mathematically coherent approach to inference. There is little appreciation in the medical community that the methodology is an amalgam of incompatible elements, whose utility for scientific inference has been the subject of intense debate among statisticians for almost 70 years. This article introduces some of the key elements of that debate and traces the appeal and adverse impact of this methodology to the P value fallacy, the mistaken idea that a single number can capture both the long-run outcomes of an experiment and the evidential meaning of a single result. This argument is made as a prelude to the suggestion that another measure of evidence should be used--the Bayes factor, which properly separates issues of long-run behavior from evidential strength and allows the integration of background knowledge with statistical findings.
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            Bayesian methods in meta-analysis and evidence synthesis.

            This paper reviews the use of Bayesian methods in meta-analysis. Whilst there has been an explosion in the use of meta-analysis over the last few years, driven mainly by the move towards evidence-based healthcare, so too Bayesian methods are being used increasingly within medical statistics. Whilst in many meta-analysis settings the Bayesian models used mirror those previously adopted in a frequentist formulation, there are a number of specific advantages conferred by the Bayesian approach. These include: full allowance for all parameter uncertainty in the model, the ability to include other pertinent information that would otherwise be excluded, and the ability to extend the models to accommodate more complex, but frequently occurring, scenarios. The Bayesian methods discussed are illustrated by means of a meta-analysis examining the evidence relating to electronic fetal heart rate monitoring and perinatal mortality in which evidence is available from a variety of sources.
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              The Ketogenic Diet Is an Effective Adjuvant to Radiation Therapy for the Treatment of Malignant Glioma

              Introduction The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that alters metabolism by increasing the level of ketone bodies in the blood. KetoCal® (KC) is a nutritionally complete, commercially available 4∶1 (fat∶ carbohydrate+protein) ketogenic formula that is an effective non-pharmacologic treatment for the management of refractory pediatric epilepsy. Diet-induced ketosis causes changes to brain homeostasis that have potential for the treatment of other neurological diseases such as malignant gliomas. Methods We used an intracranial bioluminescent mouse model of malignant glioma. Following implantation animals were maintained on standard diet (SD) or KC. The mice received 2×4 Gy of whole brain radiation and tumor growth was followed by in vivo imaging. Results Animals fed KC had elevated levels of β-hydroxybutyrate (p = 0.0173) and an increased median survival of approximately 5 days relative to animals maintained on SD. KC plus radiation treatment were more than additive, and in 9 of 11 irradiated animals maintained on KC the bioluminescent signal from the tumor cells diminished below the level of detection (p<0.0001). Animals were switched to SD 101 days after implantation and no signs of tumor recurrence were seen for over 200 days. Conclusions KC significantly enhances the anti-tumor effect of radiation. This suggests that cellular metabolic alterations induced through KC may be useful as an adjuvant to the current standard of care for the treatment of human malignant gliomas.
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                Author and article information

                Contributors
                +49 9721 720 2761 , rainer_klement@gmx.de
                psb@montana.edu
                champce@upmc.edu
                hwalac@googlemail.com
                Journal
                Theor Biol Med Model
                Theor Biol Med Model
                Theoretical Biology & Medical Modelling
                BioMed Central (London )
                1742-4682
                20 August 2018
                20 August 2018
                2018
                : 15
                : 12
                Affiliations
                [1 ]ISNI 0000 0004 0493 3473, GRID grid.415896.7, Department of Radiotherapy and Radiation Oncology, , Leopoldina Hospital Schweinfurt, ; Robert-Koch-Straße 10, 97422 Schweinfurt, Germany
                [2 ]ISNI 0000 0001 2156 6108, GRID grid.41891.35, Department of History & Philosophy, , Montana State University, ; Bozeman, MT USA
                [3 ]ISNI 0000 0001 0650 7433, GRID grid.412689.0, Department of Radiation Oncology, , University of Pittsburgh Medical Center, ; Pittsburgh, PA USA
                [4 ]ISNI 0000 0001 2205 0971, GRID grid.22254.33, Department of Pediatric Gastroenterology, , Medical University Poznan, ; Poznan, Poland
                [5 ]ISNI 0000 0000 9024 6397, GRID grid.412581.b, Department of Psychology, , University Witten-Herdecke, ; Witten, Germany
                Author information
                http://orcid.org/0000-0003-1401-4270
                Article
                84
                10.1186/s12976-018-0084-y
                6100754
                30122157
                3889bfb8-135c-4769-9d82-b9b01faf50a5
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 15 May 2018
                : 4 July 2018
                Categories
                Research
                Custom metadata
                © The Author(s) 2018

                Quantitative & Systems biology
                bayesian evidence synthesis,calorie restriction,evidence based medicine,high grade glioma,ketogenic diet,philosophy of medicine,philosophy of science

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