| 1. |
- Myte, Robin, et al.
(författare)
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Metabolic factors and the risk of colorectal cancer by KRAS and BRAF mutation status
- 2019
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 145:2, s. 327-337
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Tidskriftsartikel (refereegranskat)abstract
- Factors related to energy metabolism and the metabolic syndrome, such as higher body mass index (BMI), blood glucose, or blood lipids, and blood pressure, are associated with an increased risk of colorectal cancer (CRC). However, CRC is a heterogeneous disease, developing through distinct pathways with differences in molecular characteristics and prognosis, and possibly also in risk factors. For subtypes defined by KRAS and BRAF mutation status, BMI is the only metabolic factor previously studied, with inconsistent findings. We investigated whether associations between BMI, blood glucose, blood lipids, and blood pressure and CRC risk differed by tumor KRAS and BRAF mutation status in 117,687 participants from two population-based cohorts within the Northern Sweden Health and Disease Study (NSHDS). Hazard ratios (HRs) for overall CRC and CRC subtypes by metabolic factors were estimated with Cox proportional hazards regression, using multiple imputation to handle missing exposure and tumor data. During a median follow-up of 15.6 years, we acquired 1,250 prospective CRC cases, of which 766 cases had complete baseline and molecular tumor data. Consistent with previous evidence, higher BMI, total cholesterol, triglyceride levels, and blood pressure were associated with an increased risk of overall CRC (HRs per 1 standard deviation increase: 1.07 to 1.12). These associations were similar regardless of CRC subtype by KRAS and BRAF mutation status (all pheterogeneity > 0.05). The same was true for subtypes based on microsatellite instability status. Poor metabolic health may therefore be a universal mechanism for colorectal cancer, acting across multiple developmental pathways.
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| 2. |
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| 3. |
- Andersson, Jenny, 1976, et al.
(författare)
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The Volume Fraction of a Non-overlapping Germ-grain Model
- 2006
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Ingår i: Electronic Communications in Probability. - 1083-589X. ; 11, s. 78-88
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Tidskriftsartikel (refereegranskat)abstract
- We discuss the volume fraction of a model of non--overlapping convex grains. It is obtained from thinning a Poisson process where each point has a weight and is the centre of a grain, by removing any grain that is overlapped by one of larger or equal weight. In the limit as the intensity of the Poisson process tends to infinity, the model can be identified with the intact grains in the dead leaves model if the weights are independent of the grain sizes. In this case we can show that the volume fraction is at most $1/2^d$ for $d=1$ or $2$ if the shape is fixed, but the size and the orientation are random. The upper bound is achieved for centrally symmetric sets of the same size and orientation. For general $d$ we can show the upper bound, $1/2^d$, for spherical grains with two--point radius distribution. If dependence between weight and size is allowed, it is possible to achieve a volume fraction arbitrarily close to one.
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| 4. |
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| 5. |
- Back, Erik, et al.
(författare)
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Permanent stoma rates after anterior resection for rectal cancer : risk prediction scoring using preoperative variables
- 2021
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Ingår i: British Journal of Surgery. - : Oxford University Press. - 0007-1323 .- 1365-2168. ; 108:11, s. 1388-1395
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A permanent stoma after anterior resection for rectal cancer is common. Preoperative counselling could be improved by providing individualized accurate prediction modelling.METHODS: Patients who underwent anterior resection between 2007 and 2015 were identified from the Swedish Colorectal Cancer Registry. National Patient Registry data were added to determine presence of a stoma 2 years after surgery. A training set based on the years 2007-2013 was employed in an ensemble of prediction models. Judged by the area under the receiving operating characteristic curve (AUROC), data from the years 2014-2015 were used to evaluate the predictive ability of all models. The best performing model was subsequently implemented in typical clinical scenarios and in an online calculator to predict the permanent stoma risk.RESULTS: Patients in the training set (n = 3512) and the test set (n = 1136) had similar permanent stoma rates (13.6 and 15.2 per cent). The logistic regression model with a forward/backward procedure was the most parsimonious among several similarly performing models (AUROC 0.67, 95 per cent c.i. 0.63 to 0.72). Key predictors included co-morbidity, local tumour category, presence of metastasis, neoadjuvant therapy, defunctioning stoma use, tumour height, and hospital volume; the interaction between age and metastasis was also predictive.CONCLUSION: Using routinely available preoperative data, the stoma outcome at 2 years after anterior resection for rectal cancer can be predicted fairly accurately.
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| 6. |
- Barros, Guilherme, et al.
(författare)
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Covariate selection for the estimation of marginal hazard ratios in high-dimensional data
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Hazard ratios are frequently reported in time-to-event and epidemiological studies to assess treatment effects. In observational studies, the combination of propensity score weights with the Cox proportional hazards model facilitates the estimation of the marginal hazard ratio (MHR). The methods for estimating MHR are analogous to those employed for estimating common causal parameters, such as the average treatment effect. However, MHR estimation in the context of high-dimensional data remain unexplored. This paper seeks to address this gap through a simulation study that consider variable selection methods from causal inference combined with a recently proposed multiply robust approach for MHR estimation. Additionally, a case study utilizing stroke register data is conducted to demonstrate the application of these methods. The results from the simulation study indicate that the double selection covariate selection method is preferable to several other strategies when estimating MHR. Nevertheless, the estimation can be further improved by employing the multiply robust approach to the set of propensity score models obtained during the double selection process.
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| 7. |
- Barros, Guilherme, 1992-
(författare)
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Estimation of hazard ratios from observational data with applications related to stroke
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The objective of this thesis is to examine some challenges that may emerge when conducting time-to-event studies based on observational data. Time-to-event (also called survival) is a setting that involves analyzing how different factors may influence the length of time until an individual experiences the event of interest. This type of analysis is commonly applied in fields such as medical research and epidemiology. In this thesis, which focuses on stroke, we are interested in the time to a recurrent stroke or the death of a patient who survived a first stroke.Hazard ratios are one of the main parameters estimated in time-to-event studies. Hazard ratios involve comparing the risk of experiencing the event between two groups, usually a treated group and an untreated group. They can also involve other factors, such as different age groups. Hazard ratios can be estimated from the data by using the Cox regression model.Observational data, in contrast to experimental data, involves data collected without any intervention or random assignment of treatment to the individuals. Confounders, that is, variables that distort or obscure the true relationship between treatment and outcome, are always present and need to be controlled for in observational studies.National registers are an important source of observational data. A national registry is a centralized database or system that collects, stores, and maintains information about a specific population or group of individuals within a country. Sweden is known for its detailed and complete national registers. In this thesis, data from the Swedish Stroke Register (Riksstroke) is used to study factors related to stroke.In time-to-event studies involving observational data, several challenges may arise for the researcher during data analysis. Some individuals may not experience the event during the observation period and thus the information about their time until the event is incomplete. These individuals are considered as censored. Some individuals may experience another event rather than the one of interest, a competing risk. Additionally, models must be properly constructed, with researchers selecting variables and determining the suitable functional form.Four papers are included in the thesis. Paper I demonstrates how to handle competing risks in survival analysis. The study involves comparing individuals with and without standard modifiable risk factors and their risks of a recurrent stroke or death using data from the Swedish Stroke Register.The estimation of marginal hazard ratios is a common theme in the other three papers. All involve simulation studies in order to extend methods and explore best practices when estimating marginal hazard ratios.Paper II explores non-parametric methods that can be used as alternatives to more traditional parametric methods when balancing datasets in order to estimate a marginal hazard ratio. A case study was also conducted using data from the Swedish Stroke Register involving the prescription of anticoagulants at hospital discharge after a stroke.Paper III is about how censoring affects marginal hazard ratio estimation, even with perfect balancing of the dataset. We study this issue, taking into consideration varying effect sizes and censoring rates. A procedure to attenuate the problem is also studied.Paper IV concerns covariate selection in the case of high-dimensional data. High-dimensional data involves cases in which the number of covariates in the study is comparable to the number of individuals, and therefore covariate selection methods are needed. In the paper, we explore some of these methods and suggest a best-performing procedure. As Paper II, Paper IV involves a case study of anticoagulant prescription using data from the Swedish Stroke Register.
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| 8. |
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| 9. |
- Barros, Guilherme W. F., et al.
(författare)
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Performance of modeling and balancing approach methods when using weights to estimate treatment effects in observational time-to-event settings
- 2023
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 18:12
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Tidskriftsartikel (refereegranskat)abstract
- In observational studies weighting techniques are often used to overcome bias due to confounding. Modeling approaches, such as inverse propensity score weighting, are popular, but often rely on the correct specification of a parametric model wherein neither balance nor stability are targeted. More recently, balancing approach methods that directly target covariate imbalances have been proposed, and these allow the researcher to explicitly set the desired balance constraints. In this study, we evaluate the finite sample properties of different modeling and balancing approach methods, when estimating the marginal hazard ratio, through Monte Carlo simulations. The use of the different methods is also illustrated by analyzing data from the Swedish stroke register to estimate the effect of prescribing oral anticoagulants on time to recurrent stroke or death in stroke patients with atrial fibrillation. In simulated scenarios with good overlap and low or no model misspecification the balancing approach methods performed similarly to the modeling approach methods. In scenarios with bad overlap and model misspecification, the modeling approach method incorporating variable selection performed better than the other methods. The results indicate that it is valuable to use methods that target covariate balance when estimating marginal hazard ratios, but this does not in itself guarantee good performance in situations with, e.g., poor overlap, high censoring, or misspecified models/balance constraints.
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| 10. |
- Boström, Petrus, et al.
(författare)
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Oncological Impact of High Vascular Tie After Surgery for Rectal Cancer : A Nationwide Cohort Study
- 2021
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Ingår i: Annals of Surgery. - : Wolters Kluwer. - 0003-4932 .- 1528-1140. ; 274:3, s. e236-e244
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The purpose of this study was to investigate the impact of tie level on oncological outcomes in rectal cancer surgery.Summary background data: Theoretically, a high tie of the inferior mesenteric artery could facilitate removal of apical node metastases and improve tumor staging accuracy. However, no appropriately sized randomized controlled trial exists and results from observational studies are not consistent.Methods: All stage I–III rectal cancer patients who underwent abdominal surgery with curative intention in 2007 to 2014 were identified and followed, using the Swedish Colorectal Cancer Registry. Primary outcome was cancer-specific survival, whereas overall and relative survival, locoregional and distant recurrence, and lymph node harvest were secondary outcomes, with high tie as exposure. We used propensity score matching to emulate a randomized controlled trial, and then performed Cox regression analyses to estimate hazard ratios (HRs) with confidence intervals (CIs).Results: Some 8287 patients remained for analysis, of which 37% had high tie surgery. After propensity score matching, the 5-year cancer-specific survival rate was overall 86% and we found no association between the level of tie and cancer-specific (HR 0.92, 95% CI 0.79–1.07) or overall (HR 0.98, 95% CI 0.89–1.08) survival, nor to locoregional (HR 0.85, 95% CI 0.59–1.23) or distant (HR 1.01, 95% CI 0.88–1.15) recurrence, nor to relative survival (HR 1.05, 95% CI 0.85–1.28). Stratification and sensitivity analyses were similarly insignificant, after adjustment for confounding. Total lymph node harvest was, however, increased after high tie surgery (P < 0.01), but no differences were seen regarding positive nodes (P = 0.72).Conclusion: In this nationwide cohort study, the level of tie did not influence any patient-oriented oncological outcome, neither overall nor in node-positive patients. This would allow the patient's anatomical configuration and the surgeon's preferences to determine the level of tie.
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| 11. |
- Chaparro, M. Pia, et al.
(författare)
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Childhood family structure and women's adult overweight risk : A longitudinal study
- 2017
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Ingår i: Scandinavian Journal of Public Health. - : SAGE Publications. - 1403-4948 .- 1651-1905. ; 45:5, s. 511-519
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Tidskriftsartikel (refereegranskat)abstract
- AIM: The aim of this study was to investigate whether women's adult overweight and obesity risk was associated with their childhood family structure, measured as their mothers' marital status history, during the women's first 18 years of life.METHODS: Using linked register data, we analyzed 30,584 primiparous women born in Sweden in 1975 who were between 19-35 years of age when their height and pre-pregnancy weight was recorded. The outcomes were women's overweight/obesity (body mass index (BMI) ≥ 25 kg/m(2)) and obesity (BMI ≥ 30 kg/m(2)) and the predictor was mothers' marital status history, which was summarized using sequence analysis. We carried out nested logistic regression models adjusting for women's age and maternal sociodemographic characteristics.RESULTS: Mothers' marital status history was summarized into six clusters: stable marriage, stable cohabitation, married then divorcing, cohabiting then separating, varied transitions, and not with father. In fully adjusted models and compared with women whose mothers belonged to the stable marriage cluster: (1) women whose mothers belonged to the other marital status clusters had higher odds of overweight/obesity (odds ratio (OR) ranging 1.15-1.19; p < 0.05); and (2) women whose mothers belonged to the stable cohabitation (OR = 1.31; 95% confidence interval (CI) = 1.14-1.52), cohabiting then separating (OR = 1.23; 95% CI = 1.01-1.49), varied transitions (OR = 1.24; 95% CI = 1.11-1.39), and not with father (OR = 1.24; 95% CI = 1.00-1.54) clusters had higher odds of obesity.CONCLUSIONS: Women whose mothers were not in stable marriage relationships had higher odds of being overweight or obese in adulthood. The finding that even women raised in the context of stable cohabitation had higher odds of being overweight or obese is intriguing as these relationships are socially accepted in Sweden.
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| 12. |
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| 13. |
- Chaparro, Pia, et al.
(författare)
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Regional inequalities in pre-pregnancy overweight and obesity in Sweden, 1992, 2000, and 2010
- 2015
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Ingår i: Scandinavian Journal of Public Health. - : SAGE Publications. - 1403-4948 .- 1651-1905. ; 43:5, s. 534-539
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To investigate regional differences and time trends in women's overweight and obesity in Sweden. Methods: Using data from the Swedish Medical Birth Register (women aged 18 years, first pregnancy only) and the Total Population Register accessed through the Umea SIMSAM Lab, age-standardized prevalence of pre-pregnancy overweight/obesity (BMI 25 kg/m(2)) and obesity (BMI 30 kg/m(2)) were estimated by county for the years 1992, 2000, and 2010. Maps were created using ArcMap v10.2.2 to display regional variations over time and logistic regression analyses were used to assess if the observed trends were significant. Results: The prevalence of pre-pregnancy overweight/obesity and obesity increased significantly in all Swedish counties between 1992, and 2010. In 2010, Sodermanland and Gotland exhibited the highest age-standardized overweight/obesity (39.7%) and obesity (15.1%) prevalence, respectively. The sharpest increases between 1992 and 2010 were observed in Vasterbotten for overweight/obesity (75% increase) and in Gotland for obesity (233% increase). Across the years, Stockholm had the lowest prevalence of overweight/obesity (26.3% in 2010) and obesity (7.3% in 2010) and one of the least steep increases in prevalence of both between 1992 and 2010. Conclusions: Substantial regional differences in pre-pregnancy overweight and obesity prevalence are apparent in Sweden. Further research should elucidate the mechanisms causing these differences.
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| 14. |
- Cipriano, Mariateresa, et al.
(författare)
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Association between cannabinoid CB1 receptor expression and Akt signalling in prostate cancer
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:6, s. e65798-
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Tidskriftsartikel (refereegranskat)abstract
- Background: In prostate cancer, tumour expression of cannabinoid CB1 receptors is associated with a poor prognosis. One explanation for this association comes from experiments with transfected astrocytoma cells, where a high CB receptor expression recruits the Akt signalling survival pathway. In the present study, we have investigated the association between CB1 receptor expression and the Akt pathway in a well-characterised prostate cancer tissue microarray.Methodology/Principal Findings: Phosphorylated Akt immunoreactivity (pAkt-IR) scores were available in the database. CB1 receptor immunoreactivity (CB1IR) was rescored from previously published data using the same scale as pAkt-IR. There was a highly significant correlation between CB1IR and pAkt-IR. Further, cases with high expression levels of both biomarkers were much more likely to have a more severe form of the disease at diagnosis than those with low expression levels. The two biomarkers had additive effects, rather than an interaction, upon disease-specific survival.Conclusions/Significance: The present study provides data that is consistent with the hypothesis that at a high CB1 receptor expression, the Akt signalling pathway becomes operative.
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| 15. |
- Claeson, Anna-Sara, 1974-, et al.
(författare)
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Levels of oxylipins, endocannabinoids and related lipids in plasma before and after low-level exposure to acrolein in healthy individuals and individuals with chemical intolerance
- 2017
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Ingår i: Prostaglandins, Leukotrienes and Essential Fatty Acids. - : Elsevier BV. - 0952-3278 .- 1532-2823. ; 121, s. 60-67
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Tidskriftsartikel (refereegranskat)abstract
- Oxylipins and endocannabinoids play important biological roles, including effects upon inflammation. It is not known whether the circulating levels of these lipids are affected by inhalation of the environmental pollutant acrolein. In the present study, we have investigated the consequences of low-level exposure to acrolein on oxylipin, endocannabinoid and related lipid levels in the plasma of healthy individuals and individuals with chemical intolerance (CI), an affliction with a suggested inflammatory origin. Participants were exposed twice (60 min) to heptane and a mixture of heptane and acrolein. Blood samples were collected before exposure, after and 24 h post-exposure. There were no overt effects of acrolein exposure on the oxylipin lipidome or endocannibinoids detectable in the bloodstream at the time points investigated. No relationship between basal levels or levels after exposure to acrolein and CI could be identified. This implicates a minor role of inflammatory mediators on the systemic level in CI.
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| 16. |
- Eriksson, Ulrika, et al.
(författare)
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Metalloproteinase activity is the sole factor responsible for the growth-promoting effect of conditioned medium in Trichoplusia ni insect cell cultures
- 2005
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Ingår i: Journal of Biotechnology. - : Elsevier BV. - 0168-1656 .- 1873-4863. ; 119:1, s. 76-86
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Tidskriftsartikel (refereegranskat)abstract
- Conditioned medium (CM) taken from a serum-free culture of Trichoplusia ni (BTI-Tn-5B 1-4, High Five) cells on days 2 and 3, shortened the lagphase and increased the maximum cell density when added to T ni cultures with low-inoculum cell density. Gel filtration fractions of CM, eluting at around 45 kDa, stimulated cell proliferation even better than CM. A protein in the gel filtration fraction was identified by N-terminal amino acid sequencing as a proteinase, related to a snake venom metalloproteinase. Casein zymography showed, multiple metalloproteinase bands between 48 and 25 kDa, as well as precursor forms above 48 kDa. Metalloproteinase bands below the main band at 48 kDa were autocatalytic degradation products. Metalloproteinase activity was the sole factor responsible for the growth stimulating effect of CM as shown by using the specific metalloproteinase inhibitor DL-thiorphan. Metalloproteinases have recently been shown to release growth factors from sequestering extracellular proteins. We propose that the metalloproteinase is involved in autocrine regulation of T ni proliferation in serum-free media. In addition, a gel filtration fraction of CM, eluting at about 10 kDa, inhibited cell growth. Apart from a lysozyme precursor protein and a cyclophilin-like protein, a kazal-type proteinase inhibitor could be identified in this fraction.
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| 17. |
- Feldman, Inna, et al.
(författare)
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Effectiveness and cost-effectiveness of the Salut Programme : a universal health promotion intervention for parents and children-protocol of a register-based retrospective observational study
- 2016
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 6:8
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: There is inadequate evidence for the effectiveness and cost-effectiveness of health promotion interventions. The Salut Programme aims to reach all parents and children in the Vasterbotten County of Sweden with a combination of health promotion interventions initiated during pregnancy and continued over the childhood period. This study protocol describes an effectiveness study and an economic evaluation study, where the ongoing Salut Programme is compared to care-as-usual over the periods of pregnancy, delivery and the child's first 2 years of life. Methods: A register-based retrospective observational study design will be used with existing data sources with respect to exposures and outcomes. Outcomes of interest are clustered at 3 points: around the child's birth, 1 month after the child's birth and 2 years after the child's birth. We will simulate an experiment by retrospectively identifying and comparing children and their parents in the geographical areas where the Salut Programme was implemented since 2006 and onwards, and the areas where the Programme was not implemented before 2009. Outcomes will be analysed and compared for the premeasure period, and the postmeasure period for both groups. Our analysis combines difference-in-difference estimation with matching. A complementary analysis will be carried out on the longitudinal subsample of mothers who gave birth at least once during each of the time periods. The economic evaluation aims to capture the wider societal costs and benefits of the Salut Programme for the first 2 years of the children's lives. Incremental costs will be compared with incremental health gains and the results will be presented as a cost-consequence analysis. Ethics and dissemination: The Regional Ethical Review Board in Umea has given clearance for the Salut Programme research (2010-63-31M). No individual's identity will be revealed when presenting results. This study will provide information that can guide decision-makers to allocate resources optimally.
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| 18. |
- Gabrielsson, Linda, et al.
(författare)
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The anti-inflammatory compound palmitoylethanolamide inhibits prostaglandin and hydroxyeicosatetraenoic acid production by a macrophage cell line
- 2017
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Ingår i: Pharmacology Research & Perspectives. - : John Wiley & Sons. - 2052-1707. ; 5:2
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Tidskriftsartikel (refereegranskat)abstract
- The anti-inflammatory agent palmitoylethanolamide (PEA) reduces cyclooxygenase (COX) activity in vivo in a model of inflammatory pain. It is not known whether the compound reduces prostaglandin production in RAW264.7 cells, whether such an action is affected by compounds preventing the breakdown of endogenous PEA, whether other oxylipins are affected, or whether PEA produces direct effects upon the COX-2 enzyme. RAW264.7 cells were treated with lipopolysaccharide and interferon-c to induce COX-2. At the level of mRNA, COX-2 was induced > 1000-fold following 24 h of the treatment. Coincubation with PEA (10 mu mol/L) did not affect the levels of COX-2, but reduced the levels of prostaglandins D-2 and E-2 as well as 11- and 15-hydroxyeicosatetraenoic acid, which can also be synthesised by a COX-2 pathway in macrophages. These effects were retained when hydrolysis of PEA to palmitic acid was blocked. Linoleic acidderived oxylipin levels were not affected by PEA. No direct effects of PEA upon the oxygenation of either arachidonic acid or 2-arachidonoylglycerol by COX-2 were found. It is concluded that in lipopolysaccharide and interferon-c-stimulated RAW264.7 cells, PEA reduces the production of COX-2-derived oxylipins in a manner that is retained when its metabolism to palmitic acid is inhibited.
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| 19. |
- Gerdin, Anders, et al.
(författare)
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Preoperative beta blockers and other drugs in relation to anastomotic leakage after anterior resection for rectal cancer
- 2024
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Ingår i: Colorectal Disease. - : John Wiley & Sons. - 1462-8910 .- 1463-1318. ; 26:5, s. 974-986
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Previous research has indicated that preoperative beta blocker therapy is associated with a decreased risk of complications after surgery for rectal cancer. This is thought to arise because of the anti-inflammatory activity of the drug. These results need to be reproduced and analyses extended to other drugs with such properties, as this information might be useful in clinical decision-making. The main aim of this work was to replicate previous findings of beta blocker use as a prognostic marker for postoperative leakage. We also investigated whether drug exposure might induce anastomotic leaks.Method: This is a retrospective multicentre cohort study, comprising 1126 patients who underwent anterior resection for rectal cancer between 2014 and 2018. The use of any preoperative beta blocker was treated as the primary exposure, while anastomotic leakage within 12 months of surgery was the outcome. Secondary exposures comprised angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, statins and metformin. Using multivariable regression, we performed a replication analysis with a predictive aim for beta blockers only, while adjustment for confounding was done in more causally oriented analyses for all drugs. We estimated incidence rate ratio (IRR) and relative risk (RR) with 95% confidence intervals (CIs).Results: Anastomotic leakage occurred in 20.6% of patients. Preoperative beta blockers were used by 22.7% of the cohort, while the leak distribution was almost identical between exposure groups. In the main replication analysis, no association could be detected (IRR 0.95, 95% CI 0.68–1.33). In the causally oriented analyses, only metformin affected the risk of leakage (RR 1.59, 95% Cl 1.31–1.92).Conclusion: While previous research has suggested that preoperative beta blocker use could be prognostic of anastomotic leakage, this study could not detect any such association. On the contrary, our results indicate that preoperative beta blocker use neither predicts nor causes anastomotic leakage after anterior resection for rectal cancer.
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| 20. |
- Golshani, P., et al.
(författare)
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The modified Glasgow Prognostic Score indicates an increased risk of anastomotic leakage after anterior resection for rectal cancer
- 2023
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Ingår i: International Journal of Colorectal Disease. - : Springer. - 0179-1958 .- 1432-1262. ; 38:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundPreoperative inflammation might cause and also be a marker for anastomotic leakage after anterior resection for rectal cancer. Available biomarker indices such as the modified Glasgow Prognostic Score (mGPS) or the C-reactive protein-to-albumin ratio (CAR) may be clinically useful for leakage assessment.MethodsPatients who underwent anterior resection for rectal cancer during 2014-2018 from a multicentre retrospective cohort were included. Data from the Swedish Colorectal Cancer registry and chart review at each hospital were collected. In a subset of patients, preoperative laboratory assessments were available, constituting the exposures mGPS and CAR. Anastomotic leakage within 12 months was the outcome. Causally oriented analyses were conducted with adjustment for confounding, as well as predictive models.ResultsA total of 418 patients were eligible for analysis. Most patients had mGPS = 0 (84.7%), while mGPS = 1 (10.8%) and mGPS = 2 (4.5%) were less common. mGPS = 2 (OR: 4.11; 95% CI: 1.69-10.03) seemed to confer anastomotic leakage, while this was not seen for mGPS = 1 (OR 1.09; 95% CI: 0.53-2.25). A cut off point of CAR > 0.36 might be indicative of leakage (OR 2.25; 95% CI: 1.21-4.19). Predictive modelling using mGPS rendered an area-under-the-curve of 0.73 (95% CI: 0.67-0.79) at most.DiscussionPreoperative inflammation seems to be involved in the development of anastomotic leakage after anterior resection for cancer. Inclusion into prediction models did not result in accurate leakage prediction, but high degrees of systemic inflammation might still be important in clinical decision-making.
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| 21. |
- Gylling, Björn, 1978-, et al.
(författare)
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One-carbon metabolite ratios as functional B-vitamin markers and in relation to colorectal cancer risk
- 2019
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 144:5, s. 947-956
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Tidskriftsartikel (refereegranskat)abstract
- Background: One-carbon metabolism biomarker are easily measured in plasma, but analyzing them one at a time in relation to disease does not take into account the interdependence of the many factors involved. The relative dynamics of major one-carbon metabolism branches can be assessed by relating the functional B-vitamin marker total homocysteine (tHcy) to transsulfuration (total cysteine) and methylation (creatinine) outputs.Objective: We validated the ratios of tHcy to total cysteine (Hcy:Cys), tHcy to creatinine (Hcy:Cre), and tHcy to cysteine to creatinine (Hcy:Cys:Cre) as functional markers of B-vitamin status. We also calculated the associations of these ratios to colorectal cancer (CRC) risk.Design: The relative contribution of potential confounders to the variance of the ratio-based B-vitamin markers was calculated by linear regression in a nested case-control study of 613 CRC cases and 1211 matched controls. Total B-vitamin status was represented by a summary score comprising Z-standardized plasma concentrations of folate, cobalamin, betaine, pyridoxal 5´-phosphate, and riboflavin. Associations with CRC risk were estimated using conditional logistic regression.Results: The ratio-based B-vitamin markers all outperformed tHcy as markers of total B-vitamin status, in both CRC cases and controls. Associations with CRC risk were similar for the ratio-based B-vitamin markers and total B-vitamin status (approximately 25% lower risk for high versus low B-vitamin status).Conclusions: Ratio-based B-vitamin markers were good predictors of total B-vitamin status, and displayed similar associations with CRC risk. Since tHcy and creatinine are routinely clinically analyzed, Hcy:Cre could be easily implemented in clinical practice to aid interpretation of tHcy results.
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| 22. |
- Hammarsten, Peter, 1977-, et al.
(författare)
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ErbB2 Receptor Immunoreactivity in Prostate Cancer : Relationship to the Androgen Receptor, Disease Severity at Diagnosis and Disease Outcome
- 2014
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Ingår i: PLOS ONE. - : Public Library Science. - 1932-6203. ; 9:9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: ErbB2 is a member of the epidermal growth factor family of tyrosine kinases that is centrally involved in the pathogenesis of prostate cancer and several studies have reported that a high expression of this protein has prognostic value. In the present study, we have investigated whether tumour ErbB2 immunoreactivity (ErbB2-IR) has clinically useful prognostic value, i.e. that it provides additional prognostic information to that provided by routine clinical tests (Gleason score, tumour stage).METHODOLOGY/PRINCIPAL FINDINGS: ErbB2-IR was measured in a well-characterised tissue microarray of tumour and non-malignant samples obtained at diagnosis. Additionally, mRNA levels of ErbB2-IR in the prostate were determined in the rat following manipulation of circulating androgen levels. Tumour ErbB2-IR was significantly associated with the downstream signalling molecule phosphorylated-Akt and with the cell proliferation marker Ki-67. The significant association of tumour ErbB2-IR with the Gleason score at diagnosis was lost when controlled for the association of both parameters with Ki-67. In the rat prostate, mRNA for ErbB2 was inversely associated with circulating androgen levels. There was no association between ErbB2-IR and the androgen receptor (AR)-IR in the tumours, but an interaction between the two parameters was seen with respect to their association with the tumour stage. Tumour ErbB2-IR was confirmed to be a prognostic marker for disease-specific survival, but it did not provide significant additive information to the Gleason score or to Ki-67.CONCLUSIONS/SIGNIFICANCE: It is concluded that tumour ErbB2-IR is of limited clinical value as a prognostic marker to aid treatment decisions, but could be of pathophysiological importance in prostate cancer.
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| 23. |
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| 24. |
- Holmgren, Klas, et al.
(författare)
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Defunctioning stomas may reduce chances of a stoma-free outcome after anterior resection for rectal cancer
- 2021
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Ingår i: Colorectal Disease. - : Blackwell Publishing. - 1462-8910 .- 1463-1318. ; 23:11, s. 2859-2869
-
Tidskriftsartikel (refereegranskat)abstract
- AIM: To investigate the conflicting consequences of faecal diversion on stoma outcomes and anastomotic leakage in anterior resection for rectal cancer, including interaction effects determined by the extent of mesorectal excision.METHOD: Anterior resections between 2007 and 2016 were identified using the Swedish Colorectal Cancer Registry. National Patient Registry data were added to determine stoma outcome 2 years after surgery. Tumour distance from the anal verge constituted a proxy for extent of mesorectal excision [total mesorectal excision (TME): ≤10 cm; partial mesorectal excision (PME): 13-15 cm]. With confounder-adjusted probit regression, the total effect of defunctioning stoma on permanent stoma, and the interaction effect of extent of mesorectal excision, were estimated together with the indirect effect through anastomotic leakage. Baseline risks, risk differences (RDs) and relative risks (RRs) were reported.RESULTS: The main study cohort included 4529 patients. Defunctioning stomas influenced the absolute permanent stoma risk (TME: RD 0.11 [95% CI 0.09-0.13]; PME: RD 0.15 [95% CI 0.13-0.16]). The baseline risk was higher in TME, with a resulting greater RR in PME (2.23 [95% CI 1.43-3.02] vs 4.36 [95% CI 3.05-5.68]). The indirect reduction in permanent stoma rates, due to the alleviating effect of faecal diversion on anastomotic leakage, was small (TME: 0.89 [95% CI 0.81-0.96]; PME: 0.96 [95% CI 0.91-1.00]).CONCLUSION: In anterior resection for rectal cancer, defunctioning stomas may reduce chances of a stoma-free outcome. Considering leakage reduction benefits, consequences of routine diversion in TME might be fairly balanced, while this seems questionable in PME.
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| 25. |
- Häggström, Jenny
(författare)
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Bandwidth selection for backfitting estimation of semiparametric additive models : a simulation study
- 2013
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Ingår i: Computational Statistics & Data Analysis. - Amsterdam : Elsevier. - 0167-9473 .- 1872-7352. ; 62, s. 136-148
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Tidskriftsartikel (refereegranskat)abstract
- A data-driven bandwidth selection method for backfitting estimation of semiparametric additive models, when the the parametric part is of main interest, is proposed. The proposed method is a double smoothing estimator of the mean-squared error of the backfitting estimator of the parametric terms. The performance of the proposed method is evaluated and compared with existing bandwidth selectors by means of a simulation study.
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| 26. |
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| 27. |
- Häggström, Jenny, et al.
(författare)
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CovSel : An R Package for Covariate Selection When Estimating Average Causal Effects
- 2015
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Ingår i: Journal of Statistical Software. - : Foundation for Open Access Statistic. - 1548-7660. ; 68:1, s. 1-20
-
Tidskriftsartikel (refereegranskat)abstract
- We describe the R package CovSel, which reduces the dimension of the covariate vector for the purpose of estimating an average causal effect under the unconfoundedness assumption. Covariate selection algorithms developed in De Luna, Waernbaum, and Richardson (2011) are implemented using model-free backward elimination. We show how to use the package to select minimal sets of covariates. The package can be used with continuous and discrete covariates and the user can choose between marginal co-ordinate hypothesis tests and kernel-based smoothing as model-free dimension reduction techniques.
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| 28. |
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| 29. |
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| 30. |
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| 31. |
- Häggström, Jenny, 1980-, et al.
(författare)
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Estimating prediction error : cross-validation vs. accumulated prediction error
- 2010
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Ingår i: Communications in statistics. Simulation and computation. - : Informa plc.. - 0361-0918 .- 1532-4141. ; 39:5, s. 880-898
-
Tidskriftsartikel (refereegranskat)abstract
- We study the validation of prediction rules such as regression models and classification algorithms through two out-of-sample strategies, cross-validation and accumulated prediction error. We use the framework of Efron (1983) where measures of prediction errors are defined as sample averages of expected errors and show through exact finite sample calculations that cross-validation and accumulated prediction error yield different smoothing parameter choices in nonparametric regression. The difference in choice does not vanish as sample size increases.
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| 32. |
- Häggström, Jenny, et al.
(författare)
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Is the Salut Programme an effective and cost-effective universal health promotion intervention for parents and their children? : a register-based retrospective observational study
- 2017
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Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 7:9
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: This study investigates the effectiveness and cost-effectiveness of the Salut Programme, a universal health promotion intervention, compared with care-as-usual, over the periods of pregnancy, delivery and the child's first 2 years of life.METHOD: We adopted a register-based retrospective observational design using existing data sources with respect to both exposures and outcomes. Health outcomes and costs were compared between geographical areas that received care-as-usual (non-Salut area) and areas where the programme was implemented (Salut area). We included mothers and their children from both the Salut and non-Salut areas if: (1) the child was born 2002-2004 (premeasure period) or (2) the child was born 2006-2008 (postmeasure period). The effectiveness study adopted two strategies: (1) a matched difference-in-difference analysis using data from all participants and (2) a longitudinal analysis restricted to mothers who had given birth twice, that is, both in the premeasure and postmeasure periods. The economic evaluation was performed from a healthcare and a limited societal perspective. Outcomes were clustered during pregnancy, delivery and birth and the child's first 2 years.RESULTS: Difference-in-difference analyses did not yield any significant effect on the outcomes. Longitudinal analyses resulted in significant positive improvement in Apgar scores, reflecting the newborn's physical condition, with more children having a normal Apgar score (1 min +3%, 5 min +1%). The cost of the programme was international dollar (INT$)308/child. From both costing perspectives, the programme yielded higher effects and lower costs than care-as-usual, being thus cost-saving (probability of around 50%).CONCLUSIONS: Our findings suggest that the Salut Programme is an effective universal intervention to improve maternal and child health, and it may be good value for money; however, there is large uncertainty around the cost estimates.
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| 33. |
- Häggström, Jenny, et al.
(författare)
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Optimal Bandwidth Selection in Observed-Score Kernel Equating
- 2014
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Ingår i: Journal of educational measurement. - : Wiley. - 0022-0655 .- 1745-3984. ; 51:2, s. 201-211
-
Tidskriftsartikel (refereegranskat)abstract
- The selection of bandwidth in kernel equating is important because it has a direct impact on the equated test scores. The aim of this article is to examine the use of double smoothing when selecting bandwidths in kernel equating and to compare double smoothing with the commonly used penalty method. This comparison was made using both an equivalent groups design and a nonequivalent group with anchor test design. The performance of the methods was evaluated through simulation studies using both symmetric and skewed score distributions. In addition, the bandwidth selection methods were applied to real data from a college admissions test. The results show that the traditional penalty method works well although double smoothing is a viable alternative because it performs reasonably well compared to the traditional method.
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| 34. |
- Häggström, Jenny, et al.
(författare)
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Potential upstream regulators of cannabinoid receptor 1 signaling in prostate cancer : A Bayesian network analysis of data from a tissue microarray
- 2014
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Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 74:11, s. 1107-1117
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND The endocannabinoid system regulates cancer cell proliferation, and in prostate cancer a high cannabinoid CB1 receptor expression is associated with a poor prognosis. Down-stream mediators of CB1 receptor signaling in prostate cancer are known, but information on potential upstream regulators is lacking. RESULTS Data from a well-characterized tumor tissue microarray were used for a Bayesian network analysis using the max-min hill-climbing method. In non-malignant tissue samples, a directionality of pEGFR (the phosphorylated form of the epidermal growth factor receptor) CB1 receptors were found regardless as to whether the endocannabinoid metabolizing enzyme fatty acid amide hydrolase (FAAH) was included as a parameter. A similar result was found in the tumor tissue, but only when FAAH was included in the analysis. A second regulatory pathway, from the growth factor receptor ErbB2 FAAH was also identified in the tumor samples. Transfection of AT1 prostate cancer cells with CB1 receptors induced a sensitivity to the growth-inhibiting effects of the CB receptor agonist CP55,940. The sensitivity was not dependent upon the level of receptor expression. Thus a high CB1 receptor expression alone does not drive the cells towards a survival phenotype in the presence of a CB receptor agonist. CONCLUSIONS The data identify two potential regulators of the endocannabinoid system in prostate cancer and allow the construction of a model of a dysregulated endocannabinoid signaling network in this tumor. Further studies should be designed to test the veracity of the predictions of the network analysis in prostate cancer and other solid tumors.
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| 35. |
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| 36. |
- Häggström, Jenny, 1980-
(författare)
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Selection of smoothing parameters with application in causal inference
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis is a contribution to the research area concerned with selection of smoothing parameters in the framework of nonparametric and semiparametric regression. Selection of smoothing parameters is one of the most important issues in this framework and the choice can heavily influence subsequent results. A nonparametric or semiparametric approach is often desirable when large datasets are available since this allow us to make fewer and weaker assumptions as opposed to what is needed in a parametric approach. In the first paper we consider smoothing parameter selection in nonparametric regression when the purpose is to accurately predict future or unobserved data. We study the use of accumulated prediction errors and make comparisons to leave-one-out cross-validation which is widely used by practitioners. In the second paper a general semiparametric additive model is considered and the focus is on selection of smoothing parameters when optimal estimation of some specific parameter is of interest. We introduce a double smoothing estimator of a mean squared error and propose to select smoothing parameters by minimizing this estimator. Our approach is compared with existing methods.The third paper is concerned with the selection of smoothing parameters optimal for estimating average treatment effects defined within the potential outcome framework. For this estimation problem we propose double smoothing methods similar to the method proposed in the second paper. Theoretical properties of the proposed methods are derived and comparisons with existing methods are made by simulations.In the last paper we apply our results from the third paper by using a double smoothing method for selecting smoothing parameters when estimating average treatment effects on the treated. We estimate the effect on BMI of divorcing in middle age. Rich data on socioeconomic conditions, health and lifestyle from Swedish longitudinal registers is used.
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| 37. |
- Häggström, Jenny, et al.
(författare)
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Targeted smoothing parameter selection for estimating average causal effects
- 2014
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Ingår i: Computational statistics (Zeitschrift). - : Springer. - 0943-4062 .- 1613-9658. ; 29:6, s. 1727-1748
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Tidskriftsartikel (refereegranskat)abstract
- The non-parametric estimation of average causal effects in observational studies often relies on controlling for confounding covariates through smoothing regression methods such as kernel, splines or local polynomial regression. Such regression methods are tuned via smoothing parameters which regulates the amount of degrees of freedom used in the fit. In this paper we propose data-driven methods for selecting smoothing parameters when the targeted parameter is an average causal effect. For this purpose, we propose to estimate the exact expression of the mean squared error of the estimators. Asymptotic approximations indicate that the smoothing parameters minimizing this mean squared error converges to zero faster than the optimal smoothing parameter for the estimation of the regression functions. In a simulation study we show that the proposed data-driven methods for selecting the smoothing parameters yield lower empirical mean squared error than other methods available such as, e.g., cross-validation.
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| 38. |
- Jonéus, Paulina, 1989-
(författare)
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Design and analysis with observational data : Protocols and modeling with the aim of causal inference
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis consists of six papers that study the design and analysis with observational data.There is a growing interest in using real-world evidence (RWE) for regulatory purposes. The belief is that observational data can make drug developmentmore efficient and speed up patient access to new drugs. Paper I presents a study protocol for a comparative effectiveness evaluation of two recently reimbursed hormonal treatments (NHTs) given to patients with advanced prostate cancer. The study protocol aims to present the study design, which is done without access to outcome data. Paper II presents the results from the same comparative effectiveness evaluation in clinical practice. The study shows the strength of using a matched sample and IV strategies simultaneously, even though a lack of precision using the IV analysis can be noticed.Paper III presents a study protocol from one of a few comparative effectiveness evaluations of the NHTs against Standard of Care (SoC). Almost no patients were prescribed any of the two drugs before June 2015, as the drugs were yet to be reimbursed, creating a possibility of using historical controls. Paper IV presents the results from the comparative effectiveness evaluation. We cannot rule out that the difference in mortality maybe due to confounding. However, using a bounding strategy of the effect, we do not have sufficient evidence to show that NHT reduces mortality compared to SoC.In Paper V, we investigate how high-dimensional data on healthcare consumption can be used when adjusting for imbalances between groups in an observational study. Our method employs a two-level neural attention model, where it is possible to include high-dimensional daily health data.Paper VI introduces the smooth transition duration model. This model allows for analysis of policy changes when the outcome of interest is the duration until some event and when the policy change introduces different regimes, i.e., before and after the change and in the proposed model, we allow for the change between regimes to be gradual.
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| 39. |
- Ju, Cheng, et al.
(författare)
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Collaborative-controlled LASSO for constructing propensity score-based estimators in high-dimensional data
- 2019
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Ingår i: Statistical Methods in Medical Research. - : Sage Publications. - 0962-2802 .- 1477-0334. ; 28:4, s. 1044-1063
-
Tidskriftsartikel (refereegranskat)abstract
- Propensity score-based estimators are increasingly used for causal inference in observational studies. However, model selection for propensity score estimation in high-dimensional data has received little attention. In these settings, propensity score models have traditionally been selected based on the goodness-of-fit for the treatment mechanism itself, without consideration of the causal parameter of interest. Collaborative minimum loss-based estimation is a novel methodology for causal inference that takes into account information on the causal parameter of interest when selecting a propensity score model. This “collaborative learning” considers variable associations with both treatment and outcome when selecting a propensity score model in order to minimize a bias-variance tradeoff in the estimated treatment effect. In this study, we introduce a novel approach for collaborative model selection when using the LASSO estimator for propensity score estimation in high-dimensional covariate settings. To demonstrate the importance of selecting the propensity score model collaboratively, we designed quasi-experiments based on a real electronic healthcare database, where only the potential outcomes were manually generated, and the treatment and baseline covariates remained unchanged. Results showed that the collaborative minimum loss-based estimation algorithm outperformed other competing estimators for both point estimation and confidence interval coverage. In addition, the propensity score model selected by collaborative minimum loss-based estimation could be applied to other propensity score-based estimators, which also resulted in substantive improvement for both point estimation and confidence interval coverage. We illustrate the discussed concepts through an empirical example comparing the effects of non-selective nonsteroidal anti-inflammatory drugs with selective COX-2 inhibitors on gastrointestinal complications in a population of Medicare beneficiaries.
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| 40. |
- Moosavi, Niloofar, et al.
(författare)
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The costs and benefits of uniformly valid causal inference with high-dimensional nuisance parameters
- 2023
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Ingår i: Statistical Science. - : Institute of Mathematical Statistics. - 0883-4237 .- 2168-8745. ; 38:1, s. 1-12
-
Tidskriftsartikel (refereegranskat)abstract
- Important advances have recently been achieved in developing procedures yielding uniformly valid inference for a low dimensional causal parameter when high-dimensional nuisance models must be estimated. In this paper, we review the literature on uniformly valid causal inference and discuss the costs and benefits of using uniformly valid inference procedures. Naive estimation strategies based on regularisation, machine learning, or a preliminary model selection stage for the nuisance models have finite sample distributions which are badly approximated by their asymptotic distributions. To solve this serious problem, estimators which converge uniformly in distribution over a class of data generating mechanisms have been proposed in the literature. In order to obtain uniformly valid results in high-dimensional situations, sparsity conditions for the nuisance models need typically to be made, although a double robustness property holds, whereby if one of the nuisance model is more sparse, the other nuisance model is allowed to be less sparse. While uniformly valid inference is a highly desirable property, uniformly valid procedures pay a high price in terms of inflated variability. Our discussion of this dilemma is illustrated by the study of a double-selection outcome regression estimator, which we show is uniformly asymptotically unbiased, but is less variable than uniformly valid estimators in the numerical experiments conducted.
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| 41. |
- Moosavi, Niloofar, 1990-
(författare)
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Valid causal inference in high-dimensional and complex settings
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The objective of this thesis is to consider some challenges that arise when conducting causal inference based on observational data. High dimensionality can occur when it is necessary to adjust for many covariates, and flexible models must be used to meet convergence assumptions. The latter may require the use of a novel machine learning estimator. Estimating nonparametrically-defined causal estimands at parametric rates and obtaining good-quality confidence intervals (with near nominal coverage) are the primary goals. Another challenge is providing a sensitivity analysis that can be applied in high-dimensional scenarios as a way of assessing the robustness of the results to missing confounders. Four papers are included in the thesis. A common theme in all the papers is covariate selection or nonparametric estimation of nuisance models. To provide insight into the performance of the approaches presented, some theoretical results are provided. Additionally, simulation studies are reported. In paper I, covariate selection is discussed as a method for removing redundant variables. This approach is compared to other strategies for variable selection that ensure reasonable confidence interval coverage. Paper II integrates variable selection into a sensitivity analysis, where the sensitivity parameter is the conditional correlation of the outcome and treatment variables. The validity of the analysis where the sensitivity parameter is small relative to the sample size is shown theoretically. In simulation settings, however, the analysis performs as expected, even for larger values of sensitivity parameters, when using a correction of the estimator of the residual variance for the outcome model. Paper IV extends the applicability of the sensitivity analysis method through the use of a different residual variance estimator and applies it to a real study of the effects of smoking during pregnancy on child birth weight. A real data problem of analysing the effect of early retirement on health outcomes is studied in Paper III. Rather than using variable selection strategies, convolutional neural networks are studied to fit the nuisance models.
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| 42. |
- Myte, Robin, et al.
(författare)
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A longitudinal study of prediagnostic metabolic biomarkers and the risk of molecular subtypes of colorectal cancer
- 2020
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- Body fatness increases the risk of colorectal cancer (CRC). Insulin resistance and altered adipokines are potential mechanisms, but previous biomarker studies have been inconsistent. Intertumoral heterogeneity might provide an explanation. We investigated insulin, C-peptide, adiponectin, and leptin in relation to CRC molecular subtypes using a nested case-control design (1010 cases, 1010 matched controls, median 12.3 years from baseline to CRC diagnosis) from the population-based Northern Sweden Health and Disease Study. Repeated samples were available from 518 participants. Risks of CRC and subtypes, defined by tumor BRAF and KRAS mutations and microsatellite instability (MSI) status, were estimated using conditional logistic regression and linear mixed models. Higher C-peptide and lower adiponectin were associated with increased CRC risk (odds ratios per standard deviation increase (95% CI): 1.11 (1.01, 1.23) and 0.91 (0.83, 1.00), respectively), though weakened when adjusted for body mass index. Insulin and leptin were not associated with CRC risk. Within-individual time trajectories were similar in cases and controls, and no subtype-specific relationships were identified (all Pheterogeneity > 0.1). Adiponectin was weakly inversely associated with the risk of KRAS-mutated (P = 0.08) but not BRAF-mutated or KRAS/BRAF-wildtype CRC, consistent with the one previous study. These findings contribute to an increased understanding of the complex role of body size in CRC.
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| 43. |
- Myte, Robin, et al.
(författare)
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Components of One-carbon Metabolism Other than Folate and Colorectal Cancer Risk
- 2016
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Ingår i: Epidemiology. - 1044-3983 .- 1531-5487. ; 27:6, s. 787-796
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Despite extensive study, the role of folate in colorectal cancer remains unclear. Research has therefore begun to address the role of other elements of the folate-methionine metabolic cycles. This study investigated factors other than folate involved in one-carbon metabolism, i.e., choline, betaine, dimethylglycine, sarcosine, and methionine and relevant polymorphisms, in relation to the risk of colorectal cancer in a population with low intakes and circulating levels of folate.METHODS: This was a prospective case-control study of 613 case subjects and 1,190 matched control subjects nested within the population-based Northern Sweden Health and Disease Study. We estimated odds ratios (OR) by conditional logistic regression, and marginal risk differences with weighted maximum likelihood estimation using incidence data from the study cohort.RESULTS: Higher plasma concentrations of methionine and betaine were associated with modest colorectal cancer risk reductions (OR [95% confidence interval {CI}] for highest versus lowest tertile: 0.76 [0.57, 0.99] and 0.72 [0.55, 0.94], respectively). Estimated marginal risk differences corresponded to approximately 200 fewer colorectal cancer cases per 100,000 individuals on average. We observed no clear associations between choline, dimethylglycine, or sarcosine and colorectal cancer risk. The inverse association of methionine was modified by plasma folate concentrations (OR [95% CI] for highest/lowest versus lowest/lowest tertile of plasma methionine/folate concentrations 0.39 [0.24, 0.64], Pinteraction = 0.06).CONCLUSIONS: In this population-based, nested case-control study with a long follow-up time from baseline to diagnosis (median: 8.2 years), higher plasma concentrations of methionine and betaine were associated with lower colorectal cancer risk. See Video Abstract at http://links.lww.com/EDE/B83.
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| 44. |
- Myte, Robin, et al.
(författare)
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Metabolic biomarkers and the risk of molecular subtypes of colorectal cancer
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Body fatness measured as high body mass index (BMI) increase the risk for colorectal cancer (CRC). The mechanisms behind the relationship are not fully understood, but might include insulin resistance and changes in adipokine concentrations produced by adipose tissue. Yet, associations between circulating biomarkers related to these mechanisms and CRC risk have been somewhat inconsistent, possibly due to CRC heterogeneity. To better understand the role of insulin resistance and adipokines in CRC development, we therefore investigated circulating biomarkers related to these mechanisms in relation to molecular subtypes of CRC.Methods: This was a prospective case-control study of 1010 cases and 1:1 matched controls nested within the population-based Northern Sweden Health and Disease Study (NSHDS). Concentrations of insulin, C-peptide, adiponectin, and leptin were quantified in prediagnostic plasma using immunoassays and related to CRC and CRC subtypes defined by mutations in BRAF and KRAS, and microsatellite instability (MSI) status analyzed in tumor tissue. Odds ratios (ORs) and 95% confidence intervals (CIs) for CRC by metabolic biomarker levels were calculated with conditional logistic regression.Results: Higher C-peptide and lower adiponectin were associated with an increased CRC risk (ORs per 1 standard deviation increase (95% CI): 1.11 (1.01, 1.23) and 0.91 (0.83, 1.00), respectively). The associations were attenuated when adjusting for BMI (ORs (95% CI): 1.07 (0.96, 1.19) and 0.93 (0.84, 1.03), respectively), with the potential exception of the association of C-peptide in women. Circulating insulin and leptin were not associated with CRC risk. We found no clear differences in the association between any biomarkers and CRC risk by molecular subtypes defined by KRAS and BRAF mutation status (Pheterogeneity>0.6), or MSI status (Pheterogeneity>0.3).Conclusion: Circulating biomarkers of insulin resistance and adipokines were not associated with CRC or specific molecular subtypes of CRC defined by KRAS and BRAF mutation or MSI status.
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| 45. |
- Myte, Robin, 1989-
(författare)
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Metabolic Risk Factors and Molecular Subtypes of Colorectal Cancer
- 2018
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Colorectal cancer (CRC) is a heterogeneous disease developing from distinct pathways, resulting in tumor subtypes with large differences in clinical and molecular characteristics. Molecular characteristics are increasingly being used clinically to guide therapy. However, whether molecular subtypes of CRC differ in etiology or risk factors is not clear. Clarifying such potential differences may lead to an improved understanding of CRC etiology, with implications for CRC prevention and screening.Aim: The aim of this thesis was to investigate whether risk factors related to energy metabolism, such as body fatness, and one-carbon metabolism, such as circulating B-vitamin status, were associated with specific subtypes of CRC defined by molecular characteristics of the tumor. Methods: These prospective studies are based on data and blood samples from cohorts within the population-based Northern Sweden Health and Disease Study (NSHDS). Prospective CRC cases with available archived tumor tissue were analyzed for key molecular features (KRAS and BRAF mutation status, Microsatellite instability (MSI) status, and CpG Island Methylator Phenotype (CIMP) status). Paper I was a cohort study of metabolic factors related to the metabolic syndrome (117 687 participants). Paper II was a nested-case control study on circulating insulin resistance-markers and adipokines (1010 cases and 1010 matched controls). Papers III and IV were nested case-control studies of one-carbon metabolism biomarkers and genetic variants (613 cases and 1190 matched controls).Results: In paper I, we observed associations between metabolic factors, such as BMI, blood pressure, and blood lipids, and CRC risk consistent with previous studies. These associations were similar regardless of tumor KRAS and BRAF mutation status. In paper II, circulating biomarkers of insulin resistance and adipokines were not associated with the risk of CRC or specific molecular subtypes of CRC defined by KRAS and BRAF mutation or MSI status. In paper III, higher circulating levels of metabolites involved in the methionine cycle (namely, betaine and methionine) were associated with a lower CRC risk. In paper IV, we found no support for clear subtype-specific roles of any circulating one-carbon metabolism biomarker or genetic variants in CRC development.Conclusions: The result of these prospective studies suggests that metabolic factors related to energy metabolism and one-carbon metabolism are generally associated with the risk of CRC, regardless of major subtypes defined by key molecular tumor features. If causal, metabolic risk factors likely influence the risk of colorectal cancer through more than one carcinogenic pathway.
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| 46. |
- Myte, Robin, et al.
(författare)
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One-carbon metabolism biomarkers and genetic variants in relation to colorectal cancer risk by KRAS and BRAF mutation status
- 2018
-
Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 13:4
-
Tidskriftsartikel (refereegranskat)abstract
- Disturbances in one-carbon metabolism, intracellular reactions involved in nucleotide synthesis and methylation, likely increase the risk of colorectal cancer (CRC). However, results have been inconsistent. To explore whether this inconsistency could be explained by intertumoral heterogeneity, we evaluated a comprehensive panel of one-carbon metabolism biomarkers and some single nucleotide polymorphisms (SNPs) in relation to the risk of molecular subtypes of CRC defined by mutations in the KRAS and BRAF oncogenes. This nested case-control study included 488 CRC cases and 947 matched controls from two population-based cohorts in the Northern Sweden Health and Disease Study. We analyzed 14 biomarkers and 17 SNPs in prediagnostic blood and determined KRAS and BRAF mutation status in tumor tissue. In a multivariate network analysis, no variable displayed a strong association with the risk of specific CRC subtypes. A non-synonymous SNP in the CTH gene, rs1021737, had a stronger association compared with other variables. In subsequent univariate analyses, participants with variant rs1021737 genotype had a decreased risk of KRAS-mutated CRC (OR per allele = 0.72, 95% CI = 0.50, 1.05), and an increased risk of BRAF-mutated CRC (OR per allele = 1.56, 95% CI = 1.07, 2.30), with weak evidence for heterogeneity (Pheterogeneity = 0.01). This subtype-specific SNP association was not replicated in a case-case analysis of 533 CRC cases from The Cancer Genome Atlas (P = 0.85). In conclusion, we found no support for clear subtype-specific roles of one-carbon metabolism biomarkers and SNPs in CRC development, making differences in CRC molecular subtype distributions an unlikely explanation for the varying results on the role of one-carbon metabolism in CRC development across previous studies. Further investigation of the CTH gene in colorectal carcinogenesis with regards to KRAS and BRAF mutations or other molecular characteristics of the tumor may be warranted.
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| 47. |
- Myte, Robin, et al.
(författare)
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Untangling the role of one-carbon metabolism in colorectal cancer risk : a comprehensive Bayesian network analysis
- 2017
-
Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- The role of one-carbon metabolism (1CM), particularly folate, in colorectal cancer (CRC) development has been extensively studied, but with inconclusive results. Given the complexity of 1CM, the conventional approach, investigating components individually, may be insufficient. We used a machine learning-based Bayesian network approach to study, simultaneously, 14 circulating one-carbon metabolites, 17 related single nucleotide polymorphisms (SNPs), and several environmental factors in relation to CRC risk in 613 cases and 1190 controls from the prospective Northern Sweden Health and Disease Study. The estimated networks corresponded largely to known biochemical relationships. Plasma concentrations of folate (direct), vitamin B6 (pyridoxal 5-phosphate) (inverse), and vitamin B2 (riboflavin) (inverse) had the strongest independent associations with CRC risk. Our study demonstrates the importance of incorporating B-vitamins in future studies of 1CM and CRC development, and the usefulness of Bayesian network learning for investigating complex biological systems in relation to disease.
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| 48. |
- Otieno, Josline Adhiambo, et al.
(författare)
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Developing machine learning models to predict multi-class functional outcomes and death three months after stroke in Sweden
- 2024
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 19:5
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Tidskriftsartikel (refereegranskat)abstract
- Globally, stroke is the third-leading cause of mortality and disability combined, and one of the costliest diseases in society. More accurate predictions of stroke outcomes can guide healthcare organizations in allocating appropriate resources to improve care and reduce both the economic and social burden of the disease. We aim to develop and evaluate the performance and explainability of three supervised machine learning models and the traditional multinomial logistic regression (mLR) in predicting functional dependence and death three months after stroke, using routinely-collected data. This prognostic study included adult patients, registered in the Swedish Stroke Registry (Riksstroke) from 2015 to 2020. Riksstroke contains information on stroke care and outcomes among patients treated in hospitals in Sweden. Prognostic factors (features) included demographic characteristics, pre-stroke functional status, cardiovascular risk factors, medications, acute care, stroke type, and severity. The outcome was measured using the modified Rankin Scale at three months after stroke (a scale of 0-2 indicates independent, 3-5 dependent, and 6 dead). Outcome prediction models included support vector machines, artificial neural networks (ANN), eXtreme Gradient Boosting (XGBoost), and mLR. The models were trained and evaluated on 75% and 25% of the dataset, respectively. Model predictions were explained using SHAP values. The study included 102,135 patients (85.8% ischemic stroke, 53.3% male, mean age 75.8 years, and median NIHSS of 3). All models demonstrated similar overall accuracy (69%-70%). The ANN and XGBoost models performed significantly better than the mLR in classifying dependence with F1-scores of 0.603 (95% CI; 0.594-0.611) and 0.577 (95% CI; 0.568-0.586), versus 0.544 (95% CI; 0.545-0.563) for the mLR model. The factors that contributed most to the predictions were expectedly similar in the models, based on clinical knowledge. Our ANN and XGBoost models showed a modest improvement in prediction performance and explainability compared to mLR using routinely-collected data. Their improved ability to predict functional dependence may be of particular importance for the planning and organization of acute stroke care and rehabilitation.
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| 49. |
- Persson, Emma, 1981-, et al.
(författare)
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Data-driven algorithms for dimension reduction in causal inference
- 2017
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Ingår i: Computational Statistics & Data Analysis. - : Elsevier BV. - 0167-9473 .- 1872-7352. ; 105, s. 280-292
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Tidskriftsartikel (refereegranskat)abstract
- In observational studies, the causal effect of a treatment may be confounded with variables that are related to both the treatment and the outcome of interest. In order to identify a causal effect, such studies often rely on the unconfoundedness assumption, i.e., that all confounding variables are observed. The choice of covariates to control for, which is primarily based on subject matter knowledge, may result in a large covariate vector in the attempt to ensure that unconfoundedness holds. However, including redundant covariates can affect bias and efficiency of nonparametric causal effect estimators, e.g., due to the curse of dimensionality. In this paper, data-driven algo- rithms for the selection of sufficient covariate subsets are investigated. Under the assumption of unconfoundedness we search for minimal subsets of the covariate vector. Based on the framework of sufficient dimension reduction or kernel smoothing, the algorithms perform a backward elim- ination procedure testing the significance of each covariate. Their performance is evaluated in simulations and an application using data from the Swedish Childhood Diabetes Register is also presented.
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| 50. |
- Pulkki-Brännström, Anni-Maria, et al.
(författare)
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The equity impact of a universal child health promotion programme
- 2019
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Ingår i: European Journal of Public Health. - : Oxford University Press. - 1101-1262 .- 1464-360X. ; 29:Suppl 4, s. 103-103
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: We aimed to evaluate whether the Salut Programme, a universal child health promotion intervention, aimed to strengthen healthy lifestyles in northern Sweden, had any effect on income-related inequalities in positive birth outcomes for children and on healthcare use for children and their mothers.Methods: Mother’s residence and child’s date of birth determined whether the child and the mother belonged to the control group (areas that received care-as-usual) or the intervention group (areas with the intervention implemented from 2005), during the pre-measure period (children born 2002-2004) and the post-measure period (children born 2006-2008). The sum of parents’ taxable income was used for socioeconomic ranking. We computed the standard concentration index for six binary indicators of positive birth outcomes, and for inpatient and day patient care for children and mothers during the two years after delivery. Using a difference-in-difference approach, we assessed whether the extent of inequality changed over time between areas.Results: Income-related inequalities in child health status at birth and in child healthcare use were absent, except that full-term pregnancies were concentrated among the poor at pre-measure in the intervention group. However, mothers’ healthcare use was significantly pro-poor in the control group. The extent of inequality changed between pre- and post-measure periods for two outcomes: the pro-poor concentration of full-term pregnancies in the intervention group at pre-measure disappeared at post-measure; and an increase in pro-poor concentration of normal birth weight in the control group was not matched by a similar increase in the intervention group. Inequalities in healthcare use did not change significantly.Conclusions: Birth outcomes and child healthcare use seemed to be equitably distributed. However, the results raise concerns whether the intervention may have reduced the pro-poor concentration of positive birth outcomes.Key messagesThere are concerns that participation in universal health promotion programmes differs by socioeconomic status, although few public health interventions have been evaluated from an equity perspective.Birth outcomes and child healthcare use in Northern Sweden seemed to be equitably distributed across different socioeconomic groups.
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