Nonparametric methods for machine learning and association testing

As data collection becomes easier, non-parametric machine learning methods are increasing in popularity due to their ability to quickly discover informative data structures useful for prediction. Unsupervised clustering methods can be especially valuable for identifying subgroups in high dimensional gene expression data. Another important goal is prediction of disease or symptom outcomes from a given genotype. One way to achieve this goal is to first identify genetic factors associated with the outcome of interest. This may be especially challenging if the association is investigated in a sample with selection stratified with respect to a third variable, as occurs when studying secondary phenotypes in case-control studies. In Chapter 2 we develop a non-parametric, cluster significance testing algorithm. This algorithm compares the strength of identified clusters to the strength of spurious clusters produced from unimodal reference data. The method utilizes dimension reduction and sparse covariance estimation, making it is especially relevant for high dimensional data sets. We also extend the method to estimate the number of clusters present. The method is applied to several simulated and real-world data sets. We find it has comparable accuracy to existing methods and, in addition, can be used in a wider array of settings. We next develop a permutation-based sparse biclustering algorithm built upon the method of Witten and Tibshirani (2010) which iteratively employs a cluster significance testing step. Biclustering identifies a submatrix such that the pattern of the features for the observations within the submatrix are different than the pattern outside of the submatrix. We present simulation and real data results with comparison to existing methods illustrating the accuracy of the proposed method in assigning observations to clusters and identifying distinguishing features. In the last chapter we develop a permutation-based method for assessing the association between genetic factors and secondary phenotypes within a case control study. Conventional inverse-probability-of-sampling-weighted (IPW) regression (Monsees, Tamimi, and Kraft, 2009 and Richardson et al., 2007) may produce invalid estimates of association strength in situations where most of the variation in the secondary phenotype is found in the cases. Simulation and real data results indicate the proposed method has better type-I error rates and comparable power to the conventional IPW method and can be used to identify novel SNPs associated with clinical orofacial pain.Doctor of Philosoph

Widespread somatosensory sensitivity in naturally occurring canine model of osteoarthritis

Osteoarthritis (OA)-associated pain is a leading cause of disability. Central sensitization (CS), as a result of OA, is recognized as an important facet of human patients' chronic pain and has been measured in people using quantitative sensory testing (QST) testing. The spontaneous canine OA model has been suggested as a good translational model, but CS has not been explored in this model. In this study, QST was performed on dogs with and without spontaneous hip or stifle OA to determine whether OA is associated with CS in this model. Mechanical (von Frey and blunt pressure) and thermal (hot and cold) sensory thresholds obtained in dogs with chronic OA-associated pain (n = 31) were compared with those of normal dogs (n = 23). Dogs were phenotyped and joint-pain scored, and testing was performed at the OA-affected joint, cranial tibial muscle, and dorsal metatarsal region. QST summary data were evaluated using mixed-effect models to understand the influence of OA status and covariates, and dogs with OA and control dogs were compared. The presence of OA was strongly associated with hyperalgesia across all QST modalities at the index joint, cranial tibial muscle, and metatarsal site. Mechanical QST scores were significantly moderately negatively correlated with total joint-pain scores. The spontaneous canine OA model is associated with somatosensory sensitivity, likely indicative of CS. These data further validate the canine spontaneous OA model as an appropriate model of the human OA pain condition

Students Adding Value: Improving Patient Care Measures While Learning Valuable Population Health Skills

Medical students are potential resources for ambulatory primary care practices if learning goals can align with clinical needs. The authors introduced a quality improvement (QI) curriculum in the ambulatory clinical rotation that matched student learning expectations with practice needs. In 2016-2017, 128 students were assigned to academic, university affiliated, community health, and private practices. Student project measures were matched with appropriate outcome measures on monthly practice dashboards. Binomial mixed effects models were used to model QI measures. For university collaborative practices with student involvement, the estimated odds of a patient being screened for breast cancer in March 2017 was approximately 2 times greater than in 2016. This odds ratio was 36.2% greater than the comparable odds ratio for collaborative practices without student involvement (95% confidence interval = 22.7% to 51.2% greater). When student curriculum and assignments align with practice needs, practice metrics improve and students contribute to improvements in real-world settings

Modification of COMT-dependent pain sensitivity by psychological stress and sex

Catecholamine-O-methyltransferase (COMT) is a polymorphic gene whose variants affect enzymatic activity and pain sensitivity via adrenergic pathways. Although COMT represents one of the most studied genes in human pain genetics, findings regarding its association with pain phenotypes are not always replicated. Here, we investigated if interactions among functional COMT haplotypes, stress, and sex can modify the effect of COMT genetic variants on pain sensitivity. We tested these interactions in a cross-sectional study, including 2 cohorts, one of 2972 subjects tested for thermal pain sensitivity (Orofacial Pain: Prospective Evaluation and Risk Assessment) and one of 948 subjects with clinical acute pain after motor vehicle collision (post-motor vehicle collision). In both cohorts, the COMT high-pain sensitivity (HPS) haplotype showed robust interaction with stress and number of copies of the HPS haplotype was positively associated with pain sensitivity in nonstressed individuals, but not in stressed individuals. In the post-motor vehicle collision cohort, there was additional modification by sex: the HPS-stress interaction was apparent in males, but not in females. In summary, our findings indicate that stress and sex should be evaluated in association studies aiming to investigate the effect of COMT genetic variants on pain sensitivity

Multivariable Modeling of Phenotypic Risk Factors for First-Onset TMD: The OPPERA Prospective Cohort Study

Incidence of temporomandibular disorders (TMD) was predicted with multivariable models that used putative risk factors collected from initially TMD-free individuals in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. The 202 baseline risk factors included sociodemographic and clinical characteristics, measures of general health status, experimental pain sensitivity, autonomic function, and psychological distress. Study participants (n=2,737) were then followed prospectively for a median of 2.8 years to ascertain cases of first-onset TMD. Lasso regression and random forest models were used to predict incidence of first-onset TMD using all of the aforementioned measures. Variable importance scores identified the most important risk factors, and their relationship with TMD incidence was illustrated graphically using partial dependence plots. Two of the most important risk factors for elevated TMD incidence were greater numbers of comorbid pain conditions and greater extent of non-specific orofacial symptoms. Other important baseline risk factors were pre-existing bodily pain, heightened somatic awareness, and greater extent of pain in response to examiners’ palpation of the head, neck and body. Several demographic variables persisted as risk factors even after adjusting for other OPPERA variables, suggesting that environmental variables not measured in OPPERA may also contribute to first-onset TMD

Association of TMPRSS2-ERG gene fusion with clinical characteristics and outcomes: results from a population-based study of prostate cancer

Background: The presence of the TMPRSS2-ERG fusion gene in prostate tumors has recently been associated with an aggressive phenotype, as well as recurrence and death from prostate cancer. These associations suggest the hypothesis that the gene fusion may be used as a prognostic indicator for prostate cancer. Methods: In this study, fluorescent in situ hybridization (FISH) assays were used to assess TMPRSS2-ERG fusion status in a group of 214 prostate cancer cases from two population-based studies. The FISH assays were designed to detect both fusion type (deletion vs. translocation) and the number of fusion copies (single vs. multiple). Genotyping of four ERG and one TMPRSS2 SNPs using germline DNA was also performed in a sample of the cases (n = 127). Results: Of the 214 tumors scored for the TMPRSS2-ERG fusion, 64.5% were negative and 35.5% were positive for the fusion. Cases with the TMPRSS2-ERG fusion did not exhibit reduced prostate cancer survival (HR = 0.92, 95% CI = 0.22-3.93), nor was there a significant difference in causespecific survival when stratifying by translocation or deletion (HR = 0.84, 95% CI = 0.23-3.12) or by the number of retained fusion copies (HR = 1.22, 95% CI = .45-3.34). However, evidence for reduced prostate cancer-specific survival was apparent in those cases whose tumor had multiple copies of the fusion. The variant T allele of the TMPRSS2 SNP, rs12329760, was positively associated with TMPRSS2-ERG fusion by translocation (p = 0.05) and with multiple copies of the gene fusion (p = 0.03). Conclusion: If replicated, the results presented here may provide insight into the mechanism by which the TMPRSS2-ERG gene fusion arises and also contribute to diagnostic evaluations for determining the subset of men who will go on to develop metastatic prostate cancer.This work was supported by NIH grants RO1 CA56678, RO1 CA114524, and P50 CA97186; additional support was provided by the Fred Hutchinson Cancer Research Center and the Intramural Program of the National Human Genome Research Institute

“The problem area benefits from being seen from an own perspective” : A qualitative study about professionals’ experiences regarding adolescents’ problematic gaming and the importance of scientific research and diagnostics.

Syftet med studien var att analysera professionellas erfarenheter av ungas dataspelsproblematik samt betydelsen av forskning och diagnostisering i deras arbete. Den vetenskapsteoretiska ansats som använts i studien är hermeneutiken. Studien bygger på fyra kvalitativa semistrukturerade intervjuer med professionella inom både privata och kommunala verksamheter. I studien används Svensson, Johansson och Laanements (2008) teori om kunskapsformer i socialt arbete. Resultatet har visat att intervjupersonerna beskriver att forskningen om dataspelsproblematik inte används i någon stor utsträckning i arbetet med ungdomar. Detta beror bland annat på att intervjupersonerna anser att forskningen är ointressant och dåligt grundad samt att vissa av intervjupersonerna vill se problematiken som ett familjeproblem, en del av en större problematik. Vad som framkommer i studien är att det finns fler nackdelar än fördelar med diagnostisering av dataspelsproblematik som till exempel stigmatisering. En gemensam nämnare hos respondenterna är att de inte vill klassificera dataspelsproblematik som ett beroende. Dataspelsproblematiken framställs som ett område i behov av en definition.Dataspelsberoende, dataspelsproblematik, ungdomar, professionella, forskning, diagnostiserin

Chronotropic Index and Acute Exacerbations of Chronic Obstructive Pulmonary Disease: A Secondary Analysis of BLOCK COPD.

Rationale: The chronotropic index quantifies the proportion of the expected heart rate increase that is attained during exercise. The relationship between the chronotropic index and acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) has not been evaluated. Objectives: To determine whether a higher chronotropic index during a 6-minute walk (CI-6MW) is associated with lower risk of AECOPD and whether the CI-6MW is a marker of susceptibility to adverse effects of metoprolol in chronic obstructive pulmonary disease (COPD). Methods: We analyzed data from the BLOCK COPD (Beta-Blockers for the Prevention of AECOPDs) trial. We used Cox proportional hazards models to investigate the relationship between the CI-6MW and the time to AECOPDs. We also tested for interactions between study group assignment (metoprolol vs. placebo) and the CI-6MW on the time to AECOPDs. Results: Four hundred seventy-seven participants with exacerbation-prone COPD (mean forced expiratory volume in 1 second, 41% of predicted) were included in this analysis. A higher CI-6MW was independently associated with a decreased risk of AECOPDs of any severity (adjusted hazard ratio per 0.1 increase in CI-6MW of 0.88; 95% confidence interval, 0.80-0.96) but was not independently associated with AECOPDs requiring hospitalization (adjusted hazard ratio, 0.94; 95% confidence interval, 0.81-1.05). There was a significant interaction by treatment assignment, and in a stratified analysis, the protective effects of a higher CI-6MW on AECOPDs were negated by metoprolol use. Conclusions: A higher CI-6MW is associated with a decreased risk of AECOPDs and may be an indicator of susceptibility to the adverse effects of metoprolol

The Minnesota attributable risk of kidney donation (MARKD) study: a retrospective cohort study of long-term (> 50 year) outcomes after kidney donation compared to well-matched healthy controls

Abstract Background There is uncertainty about the long-term risks of living kidney donation. Well-designed studies with controls well-matched on risk factors for kidney disease are needed to understand the attributable risks of kidney donation. Methods The goal of the Minnesota Attributable Risk of Kidney Donation (MARKD) study is to compare the long-term (> 50 years) outcomes of living donors (LDs) to contemporary and geographically similar controls that are well-matched on health status. University of Minnesota (n = 4022; 1st transplant: 1963) and Mayo Clinic LDs (n = 3035; 1st transplant: 1963) will be matched to Rochester Epidemiology Project (REP) controls (approximately 4 controls to 1 donor) on the basis of age, sex, and race/ethnicity. The REP controls are a well-defined population, with detailed medical record data linked between all providers in Olmsted and surrounding counties, that come from the same geographic region and era (early 1960s to present) as the donors. Controls will be carefully selected to have health status acceptable for donation on the index date (date their matched donor donated). Further refinement of the control group will include confirmed kidney health (e.g., normal serum creatinine and/or no proteinuria) and matching (on index date) of body mass index, smoking history, family history of chronic kidney disease, and blood pressure. Outcomes will be ascertained from national registries (National Death Index and United States Renal Data System) and a new survey administered to both donors and controls; the data will be supplemented by prior surveys and medical record review of donors and REP controls. The outcomes to be compared are all-cause mortality, end-stage kidney disease, cardiovascular disease and mortality, estimated glomerular filtration rate (eGFR) trajectory and chronic kidney disease, pregnancy risks, and development of diseases that frequently lead to chronic kidney disease (e.g. hypertension, diabetes, and obesity). We will additionally evaluate whether the risk of donation differs based on baseline characteristics. Discussion Our study will provide a comprehensive assessment of long-term living donor risk to inform candidate living donors, and to inform the follow-up and care of current living donors