Positive Possibilities for Child and Family Welfare: Options for Expanding the Anglo-American Child Protection Paradigm

The creation of the ‘problem of child maltreatment’ and how we deal with it are best understood as particular discourses which grow out of specific histories and social configurations. The Anglo-American child protection paradigm can be viewed as a particular configuration rooted in our vision for children, families, community, and society. However, other settings have constructed quite different responses reflecting their own priorities and desired outcomes. This paper is an effort to understand the choices made in Ontario’s child protection system by examining its history and the underlying beliefs and values which have fostered its development. In addition, the paper is an attempt to counteract the sense of inevitability of this child protection approach. By discussing the many different ways in which other countries and settings work with, and think about, families and children, we will uncover a spectrum of positive possibilities which exist outside our current conceptions of child and family welfare systems

Developing Statistical Methods for Incorporating Complexity in Association Studies

Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with hundreds of human traits. Yet the common variant model tested by traditional GWAS only provides an incomplete explanation for the known genetic heritability of many traits. Many divergent methods have been proposed to address the shortcomings of GWAS, including most notably the extension of association methods into rarer variants through whole exome and whole genome sequencing. GWAS methods feature numerous simplifications designed for feasibility and ease of use, as opposed to statistical rigor. Furthermore, no systematic quantification of the performance of GWAS across all traits exists. Beyond improving the utility of data that already exist, a more thorough understanding of the performance of GWAS on common variants may elucidate flaws not in the method but rather in its implementation, which may pose a continued or growing threat to the utility of rare variant association studies now underway. This thesis focuses on systematic evaluation and incremental improvement of GWAS modeling. We collect a rich dataset containing standardized association results from all GWAS conducted on quantitative human traits, finding that while the majority of published significant results in the field do not disclose sufficient information to determine whether the results are actually valid, those that do replicate precisely in concordance with their statistical power when conducted in samples of similar ancestry and reporting accurate per-locus sample sizes. We then look to the inability of effectively all existing association methods to handle missingness in genetic data, and show that adapting missingness theory from statistics can both increase power and provide a flexible framework for extending most existing tools with minimal effort. We finally undertake novel variant association in a schizophrenia cohort from a bottleneck population. We find that the study itself is confounded by nonrandom population sampling and identity-by-descent, manifesting as batch effects correlated with outcome that remain in novel variants after all sample-wide quality control. On the whole, these results emphasize both the past and present utility and reliability of the GWAS model, as well as the extent to which lessons from the GWAS era must inform genetic studies moving forward

Assessment of the effects and limitations of the 1998 to 2008 Abbreviated Injury Scale map using a large population-based dataset

BACKGROUND: Trauma systems should consistently monitor a given trauma population over a period of time. The Abbreviated Injury Scale (AIS) and derived scores such as the Injury Severity Score (ISS) are commonly used to quantify injury severities in trauma registries. To reflect contemporary trauma management and treatment, the most recent version of the AIS (AIS08) contains many codes which differ in severity from their equivalents in the earlier 1998 version (AIS98). Consequently, the adoption of AIS08 may impede comparisons between data coded using different AIS versions. It may also affect the number of patients classified as major trauma. METHODS: The entire AIS98-coded injury dataset of a large population based trauma registry was retrieved and mapped to AIS08 using the currently available AIS98-AIS08 dictionary map. The percentage of codes which had increased or decreased in severity, or could not be mapped, was examined in conjunction with the effect of these changes to the calculated ISS. The potential for free text information accompanying AIS coding to improve the quality of AIS mapping was explored. RESULTS: A total of 128280 AIS98-coded injuries were evaluated in 32134 patients, 15471 patients of whom were classified as major trauma. Although only 4.5% of dictionary codes decreased in severity from AIS98 to AIS08, this represented almost 13% of injuries in the registry. In 4.9% of patients, no injuries could be mapped. ISS was potentially unreliable in one-third of patients, as they had at least one AIS98 code which could not be mapped. Using AIS08, the number of patients classified as major trauma decreased by between 17.3% and 30.3%. Evaluation of free text descriptions for some injuries demonstrated the potential to improve mapping between AIS versions. CONCLUSIONS: Converting AIS98-coded data to AIS08 results in a significant decrease in the number of patients classified as major trauma. Many AIS98 codes are missing from the existing AIS map, and across a trauma population the AIS08 dataset estimates which it produces are of insufficient quality to be used in practice. However, it may be possible to improve AIS98 to AIS08 mapping to the point where it is useful to established registries

Bias Characterization in Probabilistic Genotype Data and Improved Signal Detection with Multiple Imputation

Missing data are an unavoidable component of modern statistical genetics. Different array or sequencing technologies cover different single nucleotide polymorphisms (SNPs), leading to a complicated mosaic pattern of missingness where both individual genotypes and entire SNPs are sporadically absent. Such missing data patterns cannot be ignored without introducing bias, yet cannot be inferred exclusively from nonmissing data. In genome-wide association studies, the accepted solution to missingness is to impute missing data using external reference haplotypes. The resulting probabilistic genotypes may be analyzed in the place of genotype calls. A general-purpose paradigm, called Multiple Imputation (MI), is known to model uncertainty in many contexts, yet it is not widely used in association studies. Here, we undertake a systematic evaluation of existing imputed data analysis methods and MI. We characterize biases related to uncertainty in association studies, and find that bias is introduced both at the imputation level, when imputation algorithms generate inconsistent genotype probabilities, and at the association level, when analysis methods inadequately model genotype uncertainty. We find that MI performs at least as well as existing methods or in some cases much better, and provides a straightforward paradigm for adapting existing genotype association methods to uncertain data

Statistical correction of the Winner’s Curse explains replication variability in quantitative trait genome-wide association studies

Genome-wide association studies (GWAS) have identified hundreds of SNPs responsible for variation in human quantitative traits. However, genome-wide-significant associations often fail to replicate across independent cohorts, in apparent inconsistency with their apparent strong effects in discovery cohorts. This limited success of replication raises pervasive questions about the utility of the GWAS field. We identify all 332 studies of quantitative traits from the NHGRI-EBI GWAS Database with attempted replication. We find that the majority of studies provide insufficient data to evaluate replication rates. The remaining papers replicate significantly worse than expected (p < 10−14), even when adjusting for regression-to-the-mean of effect size between discovery- and replication-cohorts termed the Winner’s Curse (p < 10−16). We show this is due in part to misreporting replication cohort-size as a maximum number, rather than per-locus one. In 39 studies accurately reporting per-locus cohort-size for attempted replication of 707 loci in samples with similar ancestry, replication rate matched expectation (predicted 458, observed 457, p = 0.94). In contrast, ancestry differences between replication and discovery (13 studies, 385 loci) cause the most highly-powered decile of loci to replicate worse than expected, due to difference in linkage disequilibrium

Differences and discrepancies between 2005 and 2008 Abbreviated Injury Scale versions - time to standardise

The aim of this letter is to facilitate the standardisation of Abbreviated Injury Scale (AIS) codesets used to code injuries in trauma registries. We have compiled a definitive list of the changes which have been implemented between the AIS 2005 and Update 2008 versions. While the AIS 2008 codeset appears to have remained consistent since its release, we have identified discrepancies between the codesets in copies of AIS 2005 dictionaries. As a result, we recommend that use of the AIS 2005 should be discontinued in favour of the Update 2008 version

sFlt-1 and NTproBNP independently predict mortality in a cohort of heart failure patients.

Objective: Soluble fms-like tyrosine kinase-1 (sFlt-1) is a circulating receptor for VEGF-A. Recent reports of elevated plasma levels of sFlt-1 in coronary heart disease and heart failure (HF) motivated our study aimed at investigating the utility of sFlt-1 as a prognostic biomarker in heart failure patients. Methods: ELISA assays for sFlt-1 and NTproBNP were performed in n=858 patients from a prospective multicentre, observational study (the PEOPLE study) of outcome among patients after appropriate treatment for an episode of acute decompensated HF in New Zealand. Plasma was sampled at a baseline visit and stored at -80°C. Statistical tests were adjusted for patient age at baseline visit, skewed data were log-adjusted and the endpoint for clinical outcome analysis was all-cause death. Patients were followed for a median of 3.63 (range 0.74-5.50) years. Results: Mean baseline plasma sFlt-1 was 125 +/- 2.01 pg/ml. sFlt-1 was higher in patients with HF with reduced ejection fraction (HFrEF) (130 +/- 2.62 pg/ml, n=553) compared to those with HF with preserved EF (HFpEF) (117 +/-3.59 pg/ml, n=305; p=0.005). sFlt-1 correlated with heart rate (r=0.148, p<0.001), systolic blood pressure (r=-0.139, p<0.001) and LVEF (r=-0.088, p=0.019). A Cox proportional hazards model showed sFlt-1 was a predictor of all-cause death (HR=6.30, p<0.001) in the PEOPLE cohort independent of age, NTproBNP, ischaemic aetiology, and NYHA class (n=842, 274 deaths), established predictors of mortality in the PEOPLE cohort. Conclusion: sFlt-1 levels at baseline should be investigated further as a predictor of death; complementary to established prognostic biomarkers in heart failure

Evidence of widespread selection on standing variation in Europe at height-associated SNPs.

Strong signatures of positive selection at newly arising genetic variants are well documented in humans(1-8), but this form of selection may not be widespread in recent human evolution(9). Because many human traits are highly polygenic and partly determined by common, ancient genetic variation, an alternative model for rapid genetic adaptation has been proposed: weak selection acting on many pre-existing (standing) genetic variants, or polygenic adaptation(10-12). By studying height, a classic polygenic trait, we demonstrate the first human signature of widespread selection on standing variation. We show that frequencies of alleles associated with increased height, both at known loci and genome wide, are systematically elevated in Northern Europeans compared with Southern Europeans (P &lt; 4.3 × 10(-4)). This pattern mirrors intra-European height differences and is not confounded by ancestry or other ascertainment biases. The systematic frequency differences are consistent with the presence of widespread weak selection (selection coefficients ∼10(-3)-10(-5) per allele) rather than genetic drift alone (P &lt; 10(-15))

Gluon polarization in the proton: constraints at low x from the measurement of the double longitudinal spin asymmetry for forward-rapidity hadrons with the PHENIX detector at RHIC

In the 1980s, polarized deep inelastic lepton-nucleon scattering experiments revealed that only about a third of the proton's spin of $\frac{1}{2}\hbar$ is carried by the quarks and antiquarks, leaving physicists with the puzzle of how to account for the remaining spin. As gluons carry roughly 50\% of the proton's momentum, it seemed most logical to look to the gluon spin as another significant contributor. However, lepton-nucleon scattering experiments only access the gluon helicity distribution, $\Delta g$, through effects on the quark distributions via scaling violations. Constraining $\Delta g$ through scaling violations requires experiments that together cover a large range of $Q^{2}$. Such experiments had been carried out with unpolarized beams, leaving $g(x)$ (the unpolarized gluon distribution) relatively well-known, but the polarized experiments have only thus far provided weak constraints on $\Delta g$ in a limited momentum fraction range. With the commissioning in 2000 of the Relativistic Heavy Ion Collider, the first polarized proton-proton ($pp$) collider, and the first polarized $pp$ running in 2002, the gluon distributions could be accessed directly by studying quark-gluon and gluon-gluon interactions. In 2009, data from measurements of double longitudinal spin asymmetries, $A_{LL},$ at the STAR and PHENIX experiments through 2006 were included in a QCD global analysis performed by Daniel de Florian, Rodolfo Sassot, Marco Stratmann, and Werner Vogelsang (DSSV), yielding the first direct constraints on the gluon helicity. The DSSV group found that the contribution of the gluon spin to the proton spin was consistent with zero, but the data provided by PHENIX and STAR was all at mid-rapidity, meaning $\Delta g$ was constrained by data only a range in $x$ from 0.05 to 0.2, leaving out helicity contributions from the huge number of low-$x$ gluons. A more recent analysis by DSSV from 2014 including RHIC data through 2009 for the first time points to significant gluon polarization at intermediate momentum fractions, meaning gluon polarization measurements may be more interesting than anticipated, especially at momentum fractions where no constraints exist as of yet. A forward detector upgrade in PHENIX, the Muon Piston Calorimeter (MPC), was designed with the purpose of extending the sensitivity to $\Delta g$ to lower $x$. Monte Carlo simulations indicate that measurements of hadrons in the MPC's pseudorapidity of range $3.1<\eta<3.9$ probe asymmetric collisions between high-$x$ quarks and low-$x$ gluons, with the $x$ of the gluons reaching below 0.01 at a collision energy $\sqrt{s}=500\,GeV$. We access $\Delta g$ through measurements of $A_{LL}$ for electromagnetic clusters in the MPC; this thesis details the measurement from the Run 11 (2011) data set at $\sqrt{s}=500\,GeV$. We find $A_{LL}\approx0$, but the statistical uncertainties from this measurement mean we likely cannot resolve the small expected asymmetries. However, improved techniques for determining the relative luminosity between bunch crossings with different helicity configurations will allow data from a much larger data set in Run 13 to be most impactful in constraining $\Delta g,$ whereas previous measurements of $A_{LL}$ have had difficulties limiting the systematic uncertainty from relative luminosity. In this thesis, we begin by presenting an overview of the physics motivation for this experiment. Then, we discuss the experimental apparatus at RHIC and PHENIX, with a focus on those systems integral to our analysis. The analysis sections of the thesis cover calibration of the Muon Piston Calorimeter, a careful examination of the relative luminosity systematic uncertainty, and the process of obtaining a final physics result