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- Romagnoni, A, et al.
(författare)
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Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 10351-
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Tidskriftsartikel (refereegranskat)abstract
- Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers.
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| 4. |
- Frøbert, Anne Mette, et al.
(författare)
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Differential Changes in Circulating Steroid Hormones in Hibernating Brown Bears : Preliminary Conclusions and Caveats
- 2022
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Ingår i: Physiological and Biochemical Zoology. - : University of Chicago Press. - 1522-2152 .- 1537-5293. ; 95:5, s. 365-378
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Tidskriftsartikel (refereegranskat)abstract
- Brown bears are obese when they enter the den, and after 6 mo of hibernation and physical inactivity, bears show none of the adverse consequences of a sedentary lifestyle in humans, such as cardiovascular disease, type 2 diabetes, and kidney failure. The metabolic mechanisms that drive hibernation physiology in bears are poorly defined, but systemic endocrine regulators are likely involved. To investigate the potential role of steroid hormones, we quantified the total levels of 12 steroid hormones, the precursor cholesterol, sex hormone-binding globulin (SHBG), and corticosterone-binding globulin (CBG) in paired serum samples from subadult free-ranging Scandinavian brown bears during the active and hibernation states. During hibernation, androstenedione and testosterone were significantly decreased in subadult female bears (n=13), whereas they increased in all males but one (n=6) and therefore did not reach a significant difference. Despite this difference, SHBG increased more than 20-fold during hibernation for all bears. Compared with SHBG concentrations in humans, bear levels were very low in the active state, but during hibernation, levels equaled high levels in humans. The increased SHBG levels likely maintain a state of relative quiescence of the reproductive hormones in hibernating bears. Interestingly, the combination of SHBG and testosterone levels results in similar free bioavailable testosterone levels of 70-80 pM in both subadult and adult sexually active male bears, suggesting a role for SHBG in controlling androgen action during hibernation in males. Dehydroepiandrosterone sulfate, dihydrotestosterone, and estradiol levels were below the detection limit in all but one animal. The metabolically active glucocorticoids were significantly higher in both sexes during hibernation, whereas the inactive metabolite cortisone was reduced and CBG was low approaching the detection limit. A potential caveat is that the glucocorticoid levels might be affected by the ketamine applied in the anesthetic mixture for hibernating bears. However, increased hibernating cortisol levels have consistently been reported in both black bears and brown bears. Thus, we suggest that high glucocorticoid activity may support the hibernation state, likely serving to promote lipolysis and gluconeogenesis while limiting tissue glucose uptake to maintain a continuous glucose supply to the brain.
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| 5. |
- Mette Frøbert, Anne, et al.
(författare)
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Characterization and comparison of recombinant full-length ursine and human sex hormone-binding globulin
- 2022
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Ingår i: FEBS Open Bio. - : John Wiley & Sons. - 2211-5463. ; 12:2, s. 362-378
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Tidskriftsartikel (refereegranskat)abstract
- Sex hormone-binding globulin (SHBG) regulates the bioavailability of sex steroid hormones in the blood. Levels of SHBG increase markedly in brown bears (Ursus arctos) during hibernation, suggesting that a key regulatory role of this protein is to quench sex steroid bioavailability in hibernation physiology. To enable characterization of ursine SHBG and a cross species comparison, we established an insect cell-based expression system for recombinant full-length ursine and human SHBG. Compared with human SHBG, we observed markedly lower secretion levels of ursine SHBG, resulting in a 10-fold difference in purified protein yield. Both human and ursine recombinant SHBG appeared as dimeric proteins in solution, with a single unfolding temperature of ~58 °C. The thermal stability of ursine and human SHBG increased 5.4 and 9.5 °C, respectively, in presence of dihydrotestosterone (DHT), suggesting a difference in affinity. The dissociation constants for [3 H]DHT were determined to 0.21±0.04 nM for human and 1.32±0.10 nM for ursine SHBG, confirming a lower affinity of ursine SHBG. A similarly reduced affinity, determined from competitive steroid binding, was observed for most steroids. Overall, we found that ursine SHBG had similar characteristics to human SHBG, specifically, being a homodimeric glycoprotein capable of binding steroids with high affinity. Therefore, ursine SHBG likely has similar biological functions to those known for human SHBG. The determined properties of ursine SHBG will contribute to elucidating its potential regulatory role in hibernation physiology.
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| 6. |
- Nelson, Gregg, et al.
(författare)
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Implementation of Enhanced Recovery After Surgery (ERAS) Across a Provincial Healthcare System : The ERAS Alberta Colorectal Surgery Experience
- 2016
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Ingår i: World Journal of Surgery. - New York, USA : Springer. - 0364-2313 .- 1432-2323. ; 40:5, s. 1092-1103
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Tidskriftsartikel (refereegranskat)abstract
- Enhanced recovery after surgery (ERAS) colorectal guideline implementation has occurred primarily in standalone institutions worldwide. We implemented the guideline in a single provincial healthcare system, and our study examined the effect of the guideline on patient outcomes [length of stay (LOS), complications, and 30-day post-discharge readmissions] across a healthcare system.We compared pre- and post-guideline implementation in consecutive elective colorectal patients, a parts per thousand yen18 years, from six Alberta hospitals between February 2013 and December 2014. Participants were followed up to 30 days post discharge. We used summary statistics, to assess the LOS and complications, and multivariate regression methods to assess readmissions and to estimate cost impacts.A total of 1333 patients (350 pre- and 983 post-ERAS) were analysed. Of this number, 55 % were males. Median overall guideline compliance was 39 % in pre- and 60 % in post-ERAS patients. Median LOS was 6 days for pre-ERAS compared to 4.5 days in post-ERAS patients with the longest implementation (p value < 0.0001). Adjusted risk ratio (RR) was 1.71, 95 % CI 1.09-2.68 for 30-day readmission, comparing pre- to post-ERAS patients. The proportion of patients who developed at least one complication was significantly reduced, from pre- to post-ERAS, difference in proportions = 11.7 %, 95 % CI 2.5-21.0, p value: 0.0139. The net cost savings attributable to guideline implementation ranged between $2806 and $5898 USD per patient.The findings in our study have shown that ERAS colorectal guideline implementation within a healthcare system resulted in patient outcome improvements, similar to those obtained in smaller standalone implementations. There was a significant beneficial impact of ERAS on scarce health system resources.
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