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

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.

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

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e10396
Author(s):  
Manawa Diwekar-Joshi ◽  
Milind Watve
Keyword(s):  
Systematic Review ◽  
Steady State ◽  
Insulin Action ◽  
Causal Relation ◽  
State Level ◽  
Epidemiological Data ◽  
Cross Sectional ◽  
Glucose Levels ◽  
Clinical Action ◽  
Set Up

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.

Continuous measurement of cerebral blood flow in anesthetized cats and dogs

1981 ◽  
Vol 241 (2) ◽  
pp. H228-H234 ◽  
Author(s):  
D. W. Busija ◽  
D. D. Heistad ◽  
M. L. Marcus
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Steady State ◽  
Correlation Coefficient ◽  
Continuous Measurement ◽  
Regression Line ◽  
Blood Velocity ◽  
Cross Sectional ◽  
Cranial Window ◽  
Pial Artery

We have developed a method for virtually continuous measurement of changes in cerebral blood flow (CBF) in cats and dogs. CBF was computed by multiplying cross-sectional area (CSA) and mean blood velocity in a pial artery. CSA was determined by measuring pial artery diameter with an electronic micrometer every 2-4 s through a cranial window. Velocity was measured continuously with a pulsed Doppler crystal positioned under a pial artery. CBF was determined in 12 anesthetized cats during 1) control, 2) hypocapnia, 3) hypercapnia, and 4) hypercapnia plus hypertension. Microspheres were injected under steady-state conditions to compare the two methods. During control, the diameter of the cerebral arteries observed was 388 +/- 28 (SE) micrometers, and CBF measured with microspheres was 40 +/- 4 ml.min-1.100 g-1. CBF decreased 18 +/- 2% during hypocapnia and increased 152 +/- 36% during hypercapnia. During steady-state conditions, the correlation coefficient between changes in CBF (CSA X velocity and microspheres) was 0.94, and the slope of the regression line was 1.02. In similar studies on seven anesthetized dogs, the correlation coefficient between CSA X velocity and microspheres was 0.98, and the slope of the regression line was 0.94. We conclude that the product of CSA and blood velocity of a pial artery provides accurate on-line measurement of changes in CBF.

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

PLoS ONE ◽  
2018 ◽  
Vol 13 (10) ◽  
pp. e0204755 ◽  
Author(s):  
Suraj Chawla ◽  
Anagha Pund ◽  
Vibishan B. ◽  
Shubhankar Kulkarni ◽  
Manawa Diwekar-Joshi ◽  
...  
Keyword(s):  
Steady State ◽  
Causal Pathways ◽  
Homeostatic System

Network reconstruction based on steady-state data

2008 ◽  
Vol 45 ◽  
pp. 161-176 ◽  
Author(s):  
Eduardo D. Sontag
Keyword(s):  
Steady State ◽  
Reverse Engineering ◽  
Theoretical Method ◽  
Network Reconstruction ◽  
Quasi Steady State ◽  
State Data

This paper discusses a theoretical method for the “reverse engineering” of networks based solely on steady-state (and quasi-steady-state) data.

Association of CYP2D6*10 (c. 100 C>T) Genotype with Z-END Concentration in Patients with Breast Cancer Receiving Tamoxifen Therapy in Indonesian Population

2019 ◽  
Vol 19 (8) ◽  
pp. 1198-1206 ◽  
Author(s):  
Yenny ◽  
Sonar S. Panigoro ◽  
Denni J. Purwanto ◽  
Adi Hidayat ◽  
Melva Louisa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Steady State ◽  
Ultra Performance Liquid Chromatography ◽  
Cross Sectional Study ◽  
Threshold Concentration ◽  
Breast Cancer Patients ◽  
Cross Sectional ◽  
Significant Difference ◽  
Pcr Rflp ◽  
Liquid Chromatography Tandem Mass

Background: Tamoxifen (TAM) is a frequently used hormonal prodrug for patients with breast cancer that needs to be activated by cytochrome P450 2D6 (CYP2D6) into Zusammen-endoxifen (Z-END). Objective: The purpose of the study was to determine the association between CYP2D6*10 (c.100C>T) genotype and attainment of the plasma steady-state Z-END minimal threshold concentration (MTC) in Indonesian women with breast cancer. Methods: A cross-sectional study was performed in 125 ambulatory patients with breast cancer consuming TAM at 20 mg/day for at least 4 months. The frequency distribution of CYP2D6*10 (c.100C>T) genotypes (C/C: wild type; C/T: heterozygous mutant; T/T: homozygous mutant) was detected using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), the results of which were subsequently confirmed by sequencing. The genotypes were categorized into plasma Z- END concentrations of <5.9 ng/mL and ≥5.9 ng/mL, which were measured using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Results: Percentages of C/C, CT, and T/T genotypes were 22.4%, 29.6%, and 48.8%, respectively. Median (25-75%) Z-END concentrations in C/C, C/T, and T/T genotypes were 9.58 (0.7-6.0), 9.86 (0.7-26.6), and 3.76 (0.9-26.6) ng/mL, respectively. Statistical analysis showed a significant difference in median Z-END concentration between patients with T/T genotype and those with C/C or C/T genotypes (p<0.001). There was a significant association between CYP2D6*10 (c.100C>T) genotypes and attainment of plasma steady-state Z-END MTC (p<0.001). Conclusion: There was a significant association between CYP2D6*10 (c.100C>T) and attainment of plasma steady-state Z-END MTC in Indonesian breast cancer patients receiving TAM at a dose of 20 mg/day.

scholarly journals Mortality due to primary brain tumours in China and detection rate in people with suspected symptoms: a nationally representative cross-sectional survey

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Bin Jiang ◽  
Hongmei Liu ◽  
Dongling Sun ◽  
Haixin Sun ◽  
Xiaojuan Ru ◽  
...  
Keyword(s):  
Brain Tumour ◽  
Brain Tumours ◽  
Detection Rate ◽  
Epidemiological Data ◽  
Cross Sectional Survey ◽  
Cross Sectional ◽  
Detection Rates ◽  
Primary Brain Tumours ◽  
Symptom Screening ◽  
Nationally Representative

Abstract Background and purpose Epidemiological data on primary brain tumours (PBTs) are lacking due to the difficulty in case ascertainment among the population. Thus, we aimed to estimate mortality due to PBTs in China nationwide and the detection rate in people with suspected symptoms. Methods A multistage, complex sampling survey regarding mortality due to PBTs in Chinese individuals was carried out by reviewing all causes of death within a year. The detection rates in people with suspected symptoms were estimated based on PBT symptom screening and neurologist reviews and compared between groups by logistic regression analysis. Results Weighted mortality due to PBT was 1.6 (0.8–3.3) per 100,000 population in Chinese individuals, 1.8 (0.7–4.6) per 100,000 population in men, and 1.5 (0.5–4.5) per 100,000 population in women. Among 14,990 people with suspected symptoms, the PBT detection rate was 306.9 (95% CI 224.7–409.3) per 100,000 population in the total population, 233.0 (95% CI 135.7–373.1) per 100,000 population in men, and 376.9 (95% CI 252.4–546.3) per 100,000 population in women. People with an unsteady gait (OR 2.46; 95% CI 1.09–5.51; P=0.029), visual anomalies (3.84; 1.88–7.85; P<0.001), and headache (2.06; 1.10–3.86; P=0.023) were more likely to have a brain tumour than those without corresponding symptoms, while people with dizziness/vertigo were less likely to have a brain tumour than those without corresponding symptoms (0.45; 0.23–0.87; P=0.017). Conclusions Mortality due to PBT in China was low, with a nationwide estimate of 21,215 (10,427–43,165) deaths attributable to PBTs annually. However, the detection rate of PBTs can be greatly improved based on symptom screening in the population.

scholarly journals Identification of Polyomaviruses in Skin Cancers

Intervirology ◽  
2021 ◽  
pp. 96-102
Author(s):  
Pedro V.A. Costa ◽  
Patricia S. Ishiy ◽  
Paulo R.P. Urbano ◽  
Camila M. Romano ◽  
Stephen K. Tyring ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Normal Skin ◽  
Dermatofibrosarcoma Protuberans ◽  
Epidemiological Data ◽  
Skin Carcinogenesis ◽  
P Value ◽  
Merkel Cell ◽  
Cross Sectional ◽  
Skin Tumours ◽  
Skin Tumour

Background: Polyomaviruses (PyVs) were initially described in animals. They have also been detected in humans with some evidence that could play a role in skin carcinogenesis. Objectives: This study aimed to verify the presence of PyVs in different skin tumour samples and to make clinical correlations with patients’ epidemiological data from Clinics Hospital of Medical School of University of São Paulo, Brazil. Methods: This is a cross-sectional study. A random selection was performed of 120 patients with histopathological exams of different cutaneous neoplasms equally divided into 6 groups and 20 patients with normal skin. The available skin specimens were analysed with 2 different techniques of PCR (conventional and real time) for detection of PyV DNA. Concomitantly, retrospective analysis of the respective medical records for the collection of epidemiological data was done. Analyses suitable for categorical data were used to compare the proportion of patients in each group. Results: PyV DNA was found in 25.69% of the samples: 15% in basal cell carcinoma group, 15% in squamous cell carcinoma, 28.57% in melanoma, 15% in dermatofibrosarcoma protuberans, 13.33% in Kaposi sarcoma, 65% in Merkel cell carcinoma (MCC), and none in normal skin. Merkel cell PyV detection was statistically significant in MCC patients (p value <0.01), but no correlations were found between PyVs and others skin tumours. Conclusion: This study demonstrated the presence of PyVs in different skin tumours; however, no association of any PyVs found in any skin tumour with epidemiological data could be shown. Further studies are still needed to elucidate the mechanisms of PyVs in skin carcinogenesis.

scholarly journals Correlation of Students’ Academic Achievements at a Professional Course of Ethics and Pediatrics Clinical Practice at Mizan-Tepi University, South Nations, Nationalities and People’s Region, Ethiopia

2021 ◽  
Vol 8 ◽  
pp. 2333794X2110037
Author(s):  
Lalisa Chewaka Gamtessa
Keyword(s):  
Academic Achievement ◽  
Clinical Practice ◽  
Nursing Students ◽  
Professional Ethics ◽  
Nursing Practice ◽  
Coefficient Of Determination ◽  
Significant Positive Association ◽  
Cross Sectional ◽  
Academic Achievements ◽  
Clinical Nursing

Nursing is a respect for dignity and treating every person equally. Qualifying competent and ethical nurses requires the incorporation of a professional code of ethics with clinical nursing practice. However, no study was conducted on the relationship between professional ethics and clinical nursing practice. Therefore this study aimed to determine correlation between professional ethics and pediatrics clinical practice from an achievement perspective. Accordingly, cross-sectional study design was conducted at Mizan-Tepi University using nursing students’ academic achievements at professional ethics and pediatric practice. Collected data were entered into Epi info 7. SPSS version 21.0 was used to calculate spearman’s rho correlation ( rs) and coefficient of determination ( R2) at P  < .05. A total of 316 study participants comprising of 209 (66.14%) male and 107 (33.86%) female nursing students included in the current study. Nursing students’ academic achievements at professional ethics was significantly and positively associated with achievements at pediatrics clinical practice ( rs  = 0.4-0.6), P < .001. Linear regression results revealed 25% to 26.7% coefficient determination for regular students and 18% to 22.9% for summer nursing students. To sum up, there was a significant positive association between achievements of students at professional ethics and pediatrics clinical practice. Therefore increasing students’ academic achievement in professional ethics can further improve their achievements at pediatrics clinical practice. However, academic achievement in professional ethics explained 22.35% of the variability in achievements at pediatric clinical practice. 77.65% of the variability in pediatrics clinical practice was due to other factors that deserve another study.

scholarly journals Analysis of the relationship between periodontitis and osteoporosis/fractures: a cross-sectional study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Seok-Jin Hong ◽  
Byoung-Eun Yang ◽  
Dae-Myoung Yoo ◽  
Sung-Jae Kim ◽  
Hyo-Geun Choi ◽  
...  
Keyword(s):  
Odds Ratio ◽  
Bone Destruction ◽  
Epidemiological Data ◽  
Income Group ◽  
Cross Sectional Study ◽  
Inflammatory Factors ◽  
Sectional Study ◽  
Mineral Density ◽  
Cross Sectional ◽  
History Of

Abstract Background Chronic periodontitis is a multifactorial inflammatory disease resulting in patients exhibiting high levels of inflammatory factors causing systemic inflammatory bone destruction that may lead to osteoporosis development. The association between periodontitis and osteoporosis has been documented; however, the findings remain unclear. This study aimed to identify the association between periodontitis and osteoporosis using a cross-sectional study design and Korean Genome and Epidemiology Study (KoGES) health examinee data. Methods This cross-sectional study used epidemiological data from the KoGES during 2004–2016. Of 125,324 participants (age, 40–79 years), 9969 with periodontitis and 115,332 controls (without periodontitis) were selected. We analyzed the history of osteoporosis and fractures of all participants. All participants were examined according to age, sex, income group, obesity, smoking habits, alcohol consumption, and food intake. To analyze the odds ratio (OR) of periodontitis for those with osteoporosis and fractures, a logistic regression model was used. Results The adjusted odds ratio (aOR) of periodontitis for osteoporosis was 2.16 (95% confidence interval [CI], 2.01–2.31; P < 0.001). The aOR of periodontitis for any fracture was 1.54 (95% CI 1.46–1.62; P < 0.001). Conclusion Osteoporosis and fractures are associated with periodontitis. Performing regular oral hygiene and examinations of bone mineral density are recommended to prevent aggravation of osteoporosis and periodontitis.

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