Driver versus navigator causation in biology: the case of insulin and fasting glucose

Background In biomedicine, inferring causal relation from experimental intervention or perturbation is believed to be a more reliable approach than inferring causation from cross-sectional correlation. However, we point out here that even in interventional inference there are logical traps. In homeostatic systems, causality in a steady state can be qualitatively different from that in a perturbed state. On a broader scale there is a need to differentiate driver causality from navigator causality. A driver is essential for reaching a destination but may not have any role in deciding the destination. A navigator on the other hand has a role in deciding the destination and the path but may not be able to drive the system to the destination. The failure to differentiate between types of causalities is likely to have resulted into many misinterpretations in physiology and biomedicine. Methods We illustrate this by critically re-examining a specific case of the causal role of insulin in glucose homeostasis using five different approaches (1) Systematic review of tissue specific insulin receptor knock-outs, (2) Systematic review of insulin suppression and insulin enhancement experiments, (3) Differentiating steady state and post-meal state glucose levels in streptozotocin treated rats in primary experiments, (4) Mathematical and theoretical considerations and (5) Glucose-insulin relationship in human epidemiological data. Results All the approaches converge on the inference that although insulin action hastens the return to a steady state after a glucose load, there is no evidence that insulin action determines the steady state level of glucose. Insulin, unlike the popular belief in medicine, appears to be a driver but not a navigator for steady state glucose level. It is quite likely therefore that the current line of clinical action in the field of type 2 diabetes has limited success largely because it is based on a misinterpretation of glucose-insulin relationship. The insulin-glucose example suggests that we may have to carefully re-examine causal inferences from perturbation experiments and set up revised norms for experimental design for causal inference.

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Does insulin signalling decide glucose levels in the fasting steady state?

10.1101/553016 ◽

2019 ◽

Author(s):

Manawa Diwekar-Joshi ◽

Milind Watve

Keyword(s):

Systematic Review ◽

Steady State ◽

Glucose Homeostasis ◽

Insulin Action ◽

Insulin Signalling ◽

Meta Analysis ◽

State Level ◽

Steady State Level ◽

Knock Out ◽

Glucose Levels

AbstractRecent work has suggested that altered insulin signalling may not be central and as critical to the pathophysiology of type 2 diabetes as classically believed. We critically re-examine the role of insulin in glucose homeostasis using five different approaches namely (i) systematic review and meta-analysis of tissue specific insulin receptor knock-out experiments in rodents, (ii) systematic review and meta-analysis of insulin suppression and insulin enhancement experiments in rodents and humans, (iii) differentiating steady-state and post-meal state glucose levels in streptozotocin treated rats in primary experiments (iv) mathematical and theoretical considerations and (v) glucose insulin relationship in human epidemiological data. All the approaches converge on the inference that although insulin action is needed to reach a homeostatic steady-state of glucose in fasting condition, there is no evidence that insulin action determines the steady-state level of glucose. A wider scale implication of the analysis is in emphasizing the need to differentiate steady state causality from perturbed state causality or on a broader scale driver causality from navigator causality in biology. A driver cause is a factor which is necessary to attain a destination but does not by itself decide the destination. A navigator cause, on the other hand, is one which by itself may not be sufficient to drive the system to a destination but which plays a role in deciding the destination or direction. Insulin appears to be a driver but not a navigator for glucose homeostasis. All evidence suggests that insulin action is required for reaching a homeostatic steady state, but it does not determine the steady-state level of glucose.

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Systematic review on infection and disease caused by Thelazia callipaeda in Europe: 2001–2020

Parasite ◽

10.1051/parasite/2020048 ◽

2020 ◽

Vol 27 ◽

pp. 52

Author(s):

Beatriz do Vale ◽

Ana Patrícia Lopes ◽

Maria da Conceição Fontes ◽

Mário Silvestre ◽

Luís Cardoso ◽

...

Keyword(s):

Systematic Review ◽

Correct Diagnosis ◽

Companion Animals ◽

Epidemiological Data ◽

Thelazia Callipaeda ◽

Red Foxes ◽

Cross Sectional ◽

Treatment And Prevention ◽

Cross Sectional Studies ◽

Available Information

Cases of thelaziosis by Thelazia callipaeda have been increasing considerably in Europe throughout the 21st century, with recent emphasis on Eastern Europe. A systematic review was conducted using defined search terms across three major databases and, additionally, with the examination of the references of the 56 articles selected. Available information about epidemiological and clinical features of all cases of thelaziosis by T. callipaeda in companion animals, wildlife and humans was extracted, evaluated and subjected to qualitative and quantitative analysis. In all cross-sectional studies about dogs, cats and red foxes, males were more frequently infected than females (dogs: p = 0.0365; cats: p = 0.0164; red foxes: p = 0.0082). Adult dogs seem to be more prone to infection (p < 0.0001), as well as large-sized dogs (p < 0.0001), and companion animals that live exclusively outdoors (p < 0.0001). Dogs and red foxes involved in these cross-sectional studies harboured significantly more female than male nematodes (p < 0.0001). Thelaziosis by T. callipaeda is far from controlled in Europe. Only through updated epidemiological data, knowledge improvement and awareness can correct diagnosis and appropriate treatment and prevention be ensured to tackle this zoonosis.

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Association between eczema and major cardiovascular outcomes in population-based studies: a systematic review protocol

BMJ Open ◽

10.1136/bmjopen-2017-017979 ◽

2017 ◽

Vol 7 (9) ◽

pp. e017979 ◽

Cited By ~ 1

Author(s):

Anna Ascott ◽

Ashley M Yu ◽

Morten Schmidt ◽

Katrina Abuabara ◽

Liam Smeeth ◽

...

Keyword(s):

Systematic Review ◽

Inflammatory Diseases ◽

Data Extraction ◽

Meta Analysis ◽

Epidemiological Data ◽

Epidemiological Studies ◽

Cardiovascular Death ◽

Population Based ◽

Cardiovascular Outcomes ◽

Cross Sectional

IntroductionChronic inflammatory diseases such as eczema (also known as atopic dermatitis) have been inconsistently linked to cardiovascular disease and stroke in both mechanistic and epidemiological studies. There is a need to review the existing epidemiological data examining the association between eczema and major cardiovascular outcomes, including angina, myocardial infarction, coronary revascularisation, heart failure, cardiac arrhythmias, stroke and cardiovascular death, in order to improve our understanding of the comorbidities of eczema.Methods and analysisWe will systematically review population-based studies, including cohort, case–control and cross-sectional studies, reporting on the association between eczema and cardiovascular outcomes. We will search Medline, Embase and Global Health, from their date of inception to April 2017, using a comprehensive search strategy formulated with the help of a librarian. Two reviewers will independently screen titles and abstracts in duplicate, followed by independent data extraction and quality assessment. We will group studies by the cardiovascular outcome under study and synthesise them narratively. If sufficient numbers of homogeneous studies are returned, we will perform meta-analyses to obtain pooled effect estimates. Preferred Reporting Items for Systematic Review and Meta-Analysis will be used to inform the reporting of this study.Trial registration numberCRD42017060359.

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Frequency and distribution of neglected tropical diseases in Mozambique: a systematic review

Infectious Diseases of Poverty ◽

10.1186/s40249-019-0613-x ◽

2019 ◽

Vol 8 (1) ◽

Cited By ~ 1

Author(s):

Berta Grau-Pujol ◽

Marilia Massangaie ◽

Jorge Cano ◽

Carmen Maroto ◽

Alcino Ndeve ◽

...

Keyword(s):

Systematic Review ◽

Neglected Tropical Diseases ◽

Case Reports ◽

Grey Literature ◽

Case Series ◽

Epidemiological Data ◽

Effective Control ◽

Tropical Diseases ◽

Case Control Studies ◽

Cross Sectional

Abstract Background Neglected tropical diseases (NTDs) affect more than one billion people living in vulnerable conditions. In spite of initiatives recently contributing to fill NTDs gaps on national and local prevalence and distribution, more epidemiological data are still needed for effective control and elimination interventions. Main text Mozambique is considered one of the countries with highest NTDs burden although available data is scarce. This study aims to conduct a systematic review on published available data about the burden and distribution of the different NTDs across Mozambique since January 1950 until December 2018. We identified manuscripts from electronic databases (Pubmed, EmBase and Global Health) and paper publications and grey literature from Mozambique Ministry of Health. Manuscripts fulfilling inclusion criteria were: cross-sectional studies, ecological studies, cohorts, reports, systematic reviews, and narrative reviews capturing epidemiological information of endemic NTDs in Mozambique. Case-control studies, letters to editor, case reports and case series of imported cases were excluded. A total of 466 manuscripts were initially identified and 98 were finally included after the revision following PRISMA guidelines. Eleven NTDs were reported in Mozambique during the study span. Northern provinces (Nampula, Cabo Delgado, Niassa, Tete and Zambezia) and Maputo province had the higher number of NTDs detected. Every disease had their own report profile: while schistosomiasis have been continuously reported since 1952 until nowadays, onchocerciasis and cysticercosis last available data is from 2007 and Echinococcosis have never been evaluated in the country. Thus, both space and time gaps on NTDs epidemiology have been identified. Conclusions This review assembles NTDs burden and distribution in Mozambique. Thus, contributes to the understanding of NTDs epidemiology in Mozambique and highlights knowledge gaps. Hence, the study provides key elements to progress towards the control and interruption of transmission of these diseases in the country.

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Investigations on the Performance of Various Horizontal Ground Electrodes

Energies ◽

10.3390/en14041036 ◽

2021 ◽

Vol 14 (4) ◽

pp. 1036

Author(s):

Hanis Hamizah Hizamul-Din ◽

Normiza Mohamad Nor ◽

Nurul Nadia Ahmad ◽

Nur Farahi Idris ◽

Azwan Mahmud

Keyword(s):

Steady State ◽

Electric Field ◽

Field Enhancement ◽

Field Measurements ◽

Ionization Process ◽

Ionization Zone ◽

Cross Sectional ◽

Air Voids ◽

Time To Peak ◽

Set Up

Experimental work on grounding systems has shown that the characteristics of grounding systems under high impulse conditions are different than those obtained at steady-state conditions. Investigations on the grounding systems under high impulse conditions make it evident that ionization process could occur in soil, due to field enhancement in air voids in the soil. This process can lead to an ionization zone that reduces the impulse resistance of grounding systems (due to an enlargement of a virtually increased cross-sectional area) from its steady state. There have been many studies pointing towards the effect of various soils and the ground electrode’s arrangement on the reduction of impulse resistance from its steady state, and its decrease with increasing currents. It was, however, noted that very few studies on the effect of the configurations of horizontal ground electrodes have been performed by field measurements before. This work presents the experimental and simulated work of various configurations of ground electrodes, with spikes which are thought to enhance the ionization process in soil. In this paper, field measurement was set up, and the results of field measurements were applied with finite element method (FEM) to obtain the electric field values. It was demonstrated that with the addition of spike on the electrodes, a high electric field was computed. The time to peak current, discharged time and impulse impedance were also analyzed for various horizontal ground electrodes.

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Inferring causal pathways among three or more variables from steady-state correlations in a homeostatic system

10.1101/278101 ◽

2018 ◽

Author(s):

Suraj Chawala ◽

Anagha Pund ◽

B. Vibishan ◽

Shubhankar Kulkarni ◽

Manawa Diwekar-Joshi ◽

...

Keyword(s):

Steady State ◽

Regression Line ◽

Insulin Response ◽

Epidemiological Data ◽

Coefficient Of Determination ◽

Classical Pathway ◽

Cross Sectional ◽

State Data ◽

Causal Pathways ◽

Homeostatic System

AbstractCross-sectional correlations between two variables have limited implications for causality. We show here that in a homeostatic system with three or more inter-correlated variables, it is possible to make causal inferences from steady-state data. Every putative pathway between three variables makes a set of differential predictions that can be tested with steady state data. For example, among 3 variables, A, B and C, the coefficient of determination, is predicted by the product of and for some pathways, but not for others. Residuals from a regression line are independent of residuals from another regression for some pathways, but positively or negatively correlated for certain other pathways. Different pathways therefore have different prediction signatures, which can be used to accept or reject plausible pathways. We apply these principles to test the classical pathway leading to a hyperinsulinemic normoglycemic insulin-resistant, or pre-diabetic state using four different sets of epidemiological data. Currently, a set of indices called HOMA-IR and HOMA-β are used to represent insulin resistance and glucose-stimulated insulin response by β cells respectively. Our analysis shows that if we assume the HOMA indices to be faithful indicators, the classical pathway must in turn, be rejected. Among the populations sampled, the classical pathway and faithfulness of the HOMA indices cannot be simultaneously true. The principles and tools described here can find wide application in inferring plausible regulatory mechanisms in homeostatic systems based on epidemiological data.

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The association between dietary inflammatory index and risk of central obesity in adults: An updated systematic review and meta-analysis

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000648 ◽

2020 ◽

Vol 90 (5-6) ◽

pp. 535-552 ◽

Cited By ~ 2

Author(s):

Mahdieh Abbasalizad Farhangi ◽

Mahdi Vajdi

Keyword(s):

Systematic Review ◽

Observational Studies ◽

Central Obesity ◽

Assessment Tool ◽

Weighted Mean Difference ◽

Meta Analysis ◽

Dietary Factors ◽

Cross Sectional ◽

Inflammatory Status ◽

Obesity Indices

Abstract. Backgrounds: Central obesity, as a pivotal component of metabolic syndrome is associated with numerous co-morbidities. Dietary factors influence central obesity by increased inflammatory status. However, recent studies didn’t evaluate the association between central obesity and dietary inflammation index (DII®) that give score to dietary factors according to their inflammatory potential. In the current systematic review and meta-analysis, we summarized the studies that investigated the association between DII® with central obesity indices in the general populations. Methods: In a systematic search from PubMed, SCOPUS, Web of Sciences and Cochrane electronic databases, we collected relevant studies written in English and published until 30 October 2019. The population of included studies were apparently healthy subjects or individuals with obesity or obesity-related diseases. Observational studies that evaluated the association between DII® and indices of central obesity including WC or WHR were included. Results: Totally thirty-two studies were included; thirty studies were cross-sectional and two were cohort studies with 103071 participants. Meta-analysis of observational studies showed that higher DII® scores were associated with 1.81 cm increase in WC (Pooled weighted mean difference (WMD) = 1.813; CI: 0.785–2.841; p = 0.001). Also, a non-significant increase in the odds of having higher WC (OR = 1.162; CI: 0.95–1.43; p = 0.154) in the highest DII category was also observed. In subgroup analysis, the continent, dietary assessment tool and gender were the heterogeneity sources. Conclusion: The findings proposed that adherence to diets with high DII® scores was associated with increased WC. Further studies with interventional designs are necessary to elucidate the causality inference between DII® and central obesity indices.

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Conflict Avoidance in Old Age

GeroPsych ◽

10.1024/1662-9647/a000168 ◽

2017 ◽

Vol 30 (2) ◽

pp. 61-70 ◽

Cited By ~ 4

Author(s):

Lia Oberhauser ◽

Andreas B. Neubauer ◽

Eva-Marie Kessler

Keyword(s):

Social Support ◽

Perceived Social Support ◽

Well Being ◽

Cross Sectional Study ◽

Conflict Avoidance ◽

Subjective Well Being ◽

Sectional Study ◽

Cross Sectional ◽

Adult Lifespan ◽

Set Up

Abstract. Conflict avoidance increases across the adult lifespan. This cross-sectional study looks at conflict avoidance as part of a mechanism to regulate belongingness needs ( Sheldon, 2011 ). We assumed that older adults perceive more threats to their belongingness when they contemplate their future, and that they preventively react with avoidance coping. We set up a model predicting conflict avoidance that included perceptions of future nonbelonging, termed anticipated loneliness, and other predictors including sociodemographics, indicators of subjective well-being and perceived social support (N = 331, aged 40–87). Anticipated loneliness predicted conflict avoidance above all other predictors and partially mediated the age-association of conflict avoidance. Results suggest that belongingness regulation accounts may deepen our understanding of conflict avoidance in the second half of life.

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