Common polygenic variation enhances risk prediction for Alzheimer's disease.

The identification of subjects at high risk for Alzheimer’s disease is important for prognosis and early intervention. We investigated the polygenic architecture of Alzheimer’s disease and the accuracy of Alzheimer’s disease prediction models, including and excluding the polygenic component in the model. This study used genotype data from the powerful dataset comprising 17 008 cases and 37 154 controls obtained from the International Genomics of Alzheimer’s Project (IGAP). Polygenic score analysis tested whether the alleles identified to associate with disease in one sample set were significantly enriched in the cases relative to the controls in an independent sample. The disease prediction accuracy was investigated in a subset of the IGAP data, a sample of 3049 cases and 1554 controls (for whom APOE genotype data were available) by means of sensitivity, specificity, area under the receiver operating characteristic curve (AUC) and positive and negative predictive values. We observed significant evidence for a polygenic component enriched in Alzheimer’s disease (P = 4.9 × 10−26). This enrichment remained significant after APOE and other genome-wide associated regions were excluded (P = 3.4 × 10−19). The best prediction accuracy AUC = 78.2% (95% confidence interval 77–80%) was achieved by a logistic regression model with APOE, the polygenic score, sex and age as predictors. In conclusion, Alzheimer’s disease has a significant polygenic component, which has predictive utility for Alzheimer’s disease risk and could be a valuable research tool complementing experimental designs, including preventative clinical trials, stem cell selection and high/low risk clinical studies. In modelling a range of sample disease prevalences, we found that polygenic scores almost doubles case prediction from chance with increased prediction at polygenic extremes.

Calcium Channel Blocker Use and Risk of Prostate Cancer by TMPRSS2:ERG Gene Fusion Status

BACKGROUND: Calcium channel blockers (CCBs) may affect prostate cancer (PCa) growth by various mechanisms including those related to androgens. The fusion of the androgen-regulated gene TMPRSS2 and the oncogene ERG (TMPRSS2:ERG or T2E) is common in PCa, and prostate tumors that harbor the gene fusion are believed to represent a distinct disease subtype. We studied the association of CCB use with the risk of PCa, and molecular subtypes of PCa defined by T2E status.

METHODS: Participants were residents of King County, Washington, recruited for population-based case-control studies (1993-1996 or 2002-2005). Tumor T2E status was determined by fluorescence in situ hybridization using tumor tissue specimens from radical prostatectomy. Detailed information on use of CCBs and other variables was obtained through in-person interviews. Binomial and polytomous logistic regression were used to generate odds ratios (ORs) and 95% confidence intervals (CIs).

RESULTS: The study included 1,747 PCa patients and 1,635 age-matched controls. A subset of 563 patients treated with radical prostatectomy had T2E status determined, of which 295 were T2E positive (52%). Use of CCBs (ever vs. never) was not associated with overall PCa risk. However, among European-American men, users had a reduced risk of higher-grade PCa (Gleason scores ≥7: adjusted OR = 0.64; 95% CI: 0.44-0.95). Further, use of CCBs was associated with a reduced risk of T2E positive PCa (adjusted OR = 0.38; 95% CI: 0.19-0.78), but was not associated with T2E negative PCa.

CONCLUSIONS: This study found suggestive evidence that use of CCBs is associated with reduced relative risks for higher Gleason score and T2E positive PCa. Future studies of PCa etiology should consider etiologic heterogeneity as PCa subtypes may develop through different causal pathways. 

Evaluating statistical and machine learning methods to predict risk of in-hospital child mortality in Uganda

Thesis (Master's)--University of Washington, 2016-08

An evaluation of trace metal distribution, enrichment factors and risk in sediments of a coastal lagoon (Ria de Aveiro, Portugal)

This paper describes a sediment survey undertaken to unravel patterns of distribution and dispersion of trace metals in an Iberian Peninsula northwestern coastal lagoon (Ria de Aveiro). Cadmium, lead, chromium, copper and zinc were analyzed in bottom sediments. Geochemical normalization is performed and two different regression models for each metal versus aluminum are tested and compared using the respective enrichment factors (EF), an estimation of the relative importance of anthropogenic contributions to the studied sediments. Mean sediment quality guideline quotients (mSQGQ) are used to evaluate sediment quality and associated potential risk to biota with effects range low as empirical sediment quality guideline (SQG) in the basis for mSQGQ calculation. Additionally, the geoaccumulation index is calculated to compare studied sediment levels to global baseline levels. The application of SQGs revealed insufficient characterization capability, especially when contrasted to EF calculated from the regression methods. These pointed a mildly enriched system with localized “hot spot” areas. Therefore, it can be considered that bottom sediments in the Ria de Aveiro system are in their majority unpolluted, zinc being the only metal of concern, presenting enrichment in all four main channels. The major rivers outlets (Caster, Antuã, and Vouga) constitute point sources, thus presenting potential risk for biota. Yet, the strong tidal influence creates a damping effect by efficiently redistributing sediment bound metals.

Older Adult Injury Risk Assessment in the Driving and Occupational Environments

Thesis (Ph.D.)--University of Washington, 2016-08

Performance of protective factors assessment in risk prediction for adults: systematic review and meta-analysis

Protective factors are neglected in risk assessment in adult psychiatric and criminal justice populations. This review investigated the predictive efficacy of selected tools that assess protective factors. Five databases were searched using comprehensive terms for records up to June 2014, resulting in 17 studies (n = 2,198). Results were combined in a multilevel meta-analysis using the R (R Core Team, R: A Language and Environment for Statistical Computing, Vienna, Austria: R Foundation for Statistical Computing, 2015) metafor package (Viechtbauer, Journal of Statistical Software, 2010, 36, 1). Prediction of outcomes was poor relative to a reference category of violent offending, with the exception of prediction of discharge from secure units. There were no significant differences between the predictive efficacy of risk scales, protective scales, and summary judgments. Protective factor assessment may be clinically useful, but more development is required. Claims that use of these tools is therapeutically beneficial require testing.

Manure and sorbent fertilisers increase on-going nutrient availability relative to conventional fertilisers

The key to better nutrient efficiency is to simultaneously improve uptake and decrease losses. This study sought to achieve this balance using sorbent additions and manure nutrients (spent poultry litter; SL) compared with results obtained using conventional sources (Conv; urea nitrogen, N; and phosphate–phosphorus; P). Two experiments were conducted. Firstly, a phosphorus pot trial involving two soils (sandy and clay) based on a factorial design (Digitaria eriantha/Pennisetum clandestinum). Subsequently, a factorial N and P field trial was conducted on the clay soil (D. eriantha/Lolium rigidum). In the pot trial, sorbent additions (26.2 g of hydrotalcite [HT] g P− 1) to the Conv treatment deferred P availability (both soils) as did SL in the sandy soil. In this soil, P delivery by the Conv treatments declined rapidly, and began to fall behind the HT and SL treatments. Addition of HT increased post-trial Colwell P. In the field trial low HT-rates (3.75 and 7.5 g of HT g P− 1) plus bentonite, allowed dry matter production and nutrient uptake to match that of Conv treatments, and increased residual mineral-N. The SL treatments performed similarly to (or better than) Conv treatments regarding nutrient uptake. With successive application, HT forms may provide better supply profiles than Conv treatments. Our findings, combined with previous studies, suggest it is possible to use manures and ion-exchangers to match conventional N and P source productivity with lower risk of nutrient losses.

Effort-reward imbalance at work and the co-occurrence of lifestyle risk factors: cross-sectional survey in a sample of 36,127 public sector employees

Background In occupational life, a mismatch between high expenditure of effort and receiving few rewards may promote the co-occurrence of lifestyle risk factors, however, there is insufficient evidence to support or refute this hypothesis. The aim of this study is to examine the extent to which the dimensions of the Effort-Reward Imbalance (ERI) model – effort, rewards and ERI – are associated with the co-occurrence of lifestyle risk factors. Methods Based on data from the Finnish Public Sector Study, cross-sectional analyses were performed for 28,894 women and 7233 men. ERI was conceptualized as a ratio of effort and rewards. To control for individual differences in response styles, such as a personal disposition to answer negatively to questionnaires, occupational and organizational -level ecological ERI scores were constructed in addition to individual-level ERI scores. Risk factors included current smoking, heavy drinking, body mass index ≥25 kg/m2, and physical inactivity. Multinomial logistic regression models were used to estimate the likelihood of having one risk factor, two risk factors, and three or four risk factors. The associations between ERI and single risk factors were explored using binary logistic regression models. Results After adjustment for age, socioeconomic position, marital status, and type of job contract, women and men with high ecological ERI were 40% more likely to have simultaneously ≥3 lifestyle risk factors (vs. 0 risk factors) compared with their counterparts with low ERI. When examined separately, both low ecological effort and low ecological rewards were also associated with an elevated prevalence of risk factor co-occurrence. The results obtained with the individual-level scores were in the same direction. The associations of ecological ERI with single risk factors were generally less marked than the associations with the co-occurrence of risk factors. Conclusion This study suggests that a high ratio of occupational efforts relative to rewards may be associated with an elevated risk of having multiple lifestyle risk factors. However, an unexpected association between low effort and a higher likelihood of risk factor co-occurrence as well as the absence of data on overcommitment (and thereby a lack of full test of the ERI model) warrant caution in regard to the extent to which the entire ERI model is supported by our evidence.

Essays on Macroeconomic Trends and Cycles

This dissertation describes two studies on macroeconomic trends and cycles. The first chapter studies the impact of Information Technology (IT) on the U.S. labor market. Over the past 30 years, employment and income shares of routine-intensive occupations have declined significantly relative to nonroutine occupations, and the overall U.S. labor income share has declined relative to capital. Furthermore, the decline of routine employment has been largely concentrated during recessions and ensuing recoveries. I build a model of unbalanced growth to assess the role of computerization and IT in driving these labor market trends and cycles. I augment a neoclassical growth model with exogenous IT progress as a form of Routine-Biased Technological Change (RBTC). I show analytically that RBTC causes the overall labor income share to follow a U-shaped time path, as the monotonic decline of routine labor share is increasingly offset by the monotonic rise of nonroutine labor share and the elasticity of substitution between the overall labor and capital declines under IT progress. Quantitatively, the model explains nearly all the divergence between routine and nonroutine labor in the period 1986-2014, as well as the mild decline of the overall labor share between 1986 and the early 2000s. However, the model with IT progress alone cannot explain the accelerated decline of labor income share after the early 2000s, suggesting that other factors, such as globalization, may have played a larger role in this period. Lastly, when nonconvex labor adjustment costs are present, the model generates a stepwise decline in routine labor hours, qualitatively consistent with the data. The timing of these trend adjustments can be significantly affected by aggregate productivity shocks and concentrated in recessions. The second chapter studies the implications of loss aversion on the business cycle dynamics of aggregate consumption and labor hours. Loss aversion refers to the fact that people are distinctively more sensitive to losses than to gains. Loss averse agents are very risk averse around the reference point and exhibit asymmetric responses to positive and negative income shocks. In an otherwise standard Real Business Cycle (RBC) model, I study loss aversion in both consumption alone and consumption-and-leisure together. My results indicate that how loss aversion affects business cycle dynamics depends critically on the nature of the reference point. If, for example, the reference point is status quo, loss aversion dramatically lowers the effective inter-temporal rate of substitution and induces excessive consumption smoothing. In contrast, if the reference point is fixed at a constant level, loss aversion generates a flat region in the decision rules and asymmetric impulse responses to technology shocks. Under a reasonable parametrization, loss aversion has the potential to generate asymmetric business cycles with deeper and more prolonged recessions.

Experimentally Testing the Effect of Parent-Adolescent Conflict on HIV Risk, and Investigation of a Neurobiological Moderator of This Effect

Human immunodeficiency virus (HIV) is a condition in which immune cells become destroyed such that the body may become unable to fight off infections. Engaging in risk-taking behaviors (e.g., substance use) puts people at heightened risk for HIV infection, with mid-to-late adolescents at increasing risk (Leigh & Stall, 1993). Environmental and neurological reasons have been suggested for increased risk-taking among adolescents. First, family-level precursors such as parent-adolescent conflict have been significantly associated with and may pose risk for engaging in substance use and risk-taking (Duncan, Duncan, Biglan, & Ary, 1998). Thus, parent-adolescent conflict may be an important proximal influence on HIV risk behaviors (Lester et al., 2010; Rowe, Wang, Greenbaum, & Liddle, 2008). Yet, the temporal relation between parent-adolescent conflict and adolescent HIV risk-taking behaviors is still unknown. Second, at-risk adolescents may carry a neurobiological predisposition for engaging in trait-like expressions of disinhibited behavior and other risk-taking behaviors (Iacono, Malone, & McGue, 2008). When exposed to interpersonally stressful situations, their likelihood of engagement in HIV risk behaviors may increase. To investigate the role of parent-adolescent conflict in adolescent HIV risk-taking behaviors, 49 adolescents ages 14-17 and their parent were randomly assigned to complete a standardized discussion task to discuss a control topic or a conflict topic. Immediately after the discussion, adolescents completed a laboratory risk-taking measure. In a follow-up visit, eligible adolescents underwent electrophysiological (EEG) recording while completing a task designed to assess the presence of a neurobiological marker for behavioral disinhibition which I hypothesized would moderate the links between conflict and risk-taking. First, findings indicated that during the discussion task, adolescents in the conflict condition evidenced a significantly greater psychophysiological stress response relative to adolescents in the control condition. Second, a neurobiological marker of behavioral disinhibition moderated the relation between discussion condition and adolescent risk-taking, such that adolescents evidencing relatively high levels of a neurobiological marker related to sensation-seeking evidenced greater levels of risk-taking following the conflict condition, relative to the control condition. Lastly, I observed no significant relation between parent-adolescent conflict, the neurobiological marker of behavioral disinhibition and adolescent engagement in real-world risk-taking behavior.

Capital structure, risk and asymmetric information : theory and evidence

This paper proposes a principal-agent model between banks and firms with risk and asymmetric information. A mixed form of finance to firms is assumed. The capital structure of firms is a relevant cause for the final aggregate level of investment in the economy. In the model analyzed, there may be a separating equilibrium, which is not economically efficient, because aggregate investments fall short of the first-best level. Based on European firm-level data, an empirical model is presented which validates the result of the relevance of the capital structure of firms. The relative magnitude of equity in the capital structure makes a real difference to the profits obtained by firms in the economy.

Risk premiumin the global creditMarkets: 2006-2012

¿What have we learnt from the 2006-2012 crisis, including events such as the subprime crisis, the bankruptcy of Lehman Brothers or the European sovereign debt crisis, among others? It is usually assumed that in firms that have a CDS quotation, this CDS is the key factor in establishing the credit premiumrisk for a new financial asset. Thus, the CDS is a key element for any investor in taking relative value opportunities across a firm’s capital structure. In the first chapter we study the most relevant aspects of the microstructure of the CDS market in terms of pricing, to have a clear idea of how this market works. We consider that such an analysis is a necessary point for establishing a solid base for the rest of the chapters in order to carry out the different empirical studies we perform. In its document “Basel III: A global regulatory framework for more resilient banks and banking systems”, Basel sets the requirement of a capital charge for credit valuation adjustment (CVA) risk in the trading book and its methodology for the computation for the capital requirement. This regulatory requirement has added extra pressure for in-depth knowledge of the CDS market and this motivates the analysis performed in this thesis. The problem arises in estimating of the credit risk premium for those counterparties without a directly quoted CDS in the market. How can we estimate the credit spread for an issuer without CDS? In addition to this, given the high volatility period in the credit market in the last few years and, in particular, after the default of Lehman Brothers on 15 September 2008, we observe the presence of big outliers in the distribution of credit spread in the different combinations of rating, industry and region. After an exhaustive analysis of the results from the different models studied, we have reached the following conclusions. It is clear that hierarchical regression models fit the data much better than those of non-hierarchical regression. Furthermore,we generally prefer the median model (50%-quantile regression) to the mean model (standard OLS regression) due to its robustness when assigning the price to a new credit asset without spread,minimizing the “inversion problem”. Finally, an additional fundamental reason to prefer the median model is the typical "right skewness" distribution of CDS spreads...

Primary Joint Arthroplasty Surgery: Is the Risk of Major Bleeding Higher in Elderly Patients? A Retrospective Cohort Study

Increased risk of bleeding after major orthopedic surgery (MOS) has been widely documented in general population. However, this complication has not been studied in elderly patients. The purpose of this study is to determine whether the risk of major bleeding after MOS is higher in elderly patients, compared with those operated at a younger age. Methods: This retrospective cohort study included total hip and total knee arthroplasty patients operated during 5 consecutive years. The main outcome was the occurrence of major bleeding. Patients with other causes of bleeding were excluded. Relative risks (RRs) and confidence intervals (CIs) were calculated, anda multivariate analysis was performed. Results: A total of 1048 patients were included, 56% of patients were hip arthroplasties. At the time of surgery, 553 (53%) patients were older than 70 years. Patients aged >70 years showed an increased risk of major bleeding (RR: 2.42 [95% CI: 1.54-3.81]). For hip arthroplasty, the RR of bleeding was 2.61 (95%CI: 1.50-4.53) and 2.25 (95% CI: 1.03-4.94) for knee arthroplasty. After multivariate analysis, age was found to be independently associated with higher risk of major bleeding. Conclusion: According to European Medicines Agency criteria, patients aged 70 years are at a higher risk of major bleeding after MOS, result of a higher frequency of blood transfusions in this group of patients. Standardized protocols for blood transfusion in these patients are still required.

Handgrip strength cut-off for cardiometabolic risk index among Colombian children and adolescents : the FUPRECOL study

Abstract Objective: Evidence shows an association between muscular strength (MS) and health among youth, however low muscular strength cut-points for the detection of high metabolic risk in Latin-American populations are scarce. The aim of this study was two-fold: to explore potential age- and sex-specific thresholds of MS, for optimal cardiometabolic risk categorization among Colombian children and adolescents; and to investigate if cardiometabolic risk differed by MS group by applying the receiver operating characteristic curve (ROC) cut point. Methods: This is a secondary analysis of a cross-sectional study (the FUPRECOL study), published elsewhere. The FUPRECOL study assessments were conducted during the 2014– 2015 school year. MS was estimated by a handle dynamometer on 1,950 children and adolescents from Colombia, using the MS relative to weight (handgrip strength/body mass). A metabolic risk score was computed from the following components: waist circumference, triglycerides, HDL-c, glucose, systolic and diastolic blood pressure. ROC analysis showed a significant discriminatory accuracy of MS in identifying the low/high metabolic risk in children and adolescents and both gender. Results: In children, handgrip strength/body mass level for a low metabolic risk were 0.359 and 0.376 in girls and boys, respectively. In adolescents, these points were 0.440 and 0.447 in girls and boys, respectively. Conclusion: In conclusion, the results suggest a hypothetical MS level relative to weight for having a low metabolic risk, which could be used to identify youths at risk.