Problems for Alternative Analyses

In this chapter, an inference to the best explanation for a contextualist account of regulative freedom is completed by arguing that this analysis has significant advantages over other views. The chapter begins by looking at rival contextualist analyses, offered by Hawthorne and Rieber. After this, the contextualist account is compared to incompatibilist and compatibilist invariant analyses. In particular, the chapter offers a critical discussion of some recent developments of compatibilist analyses’ of freedom, namely, a new conditional analysis, List’s account of agential possibilities and dispositional compatibilism. It is argued that, in all cases, a contextualist account of regulative freedom is preferable.

A UGT1A1 variant is associated with serum total bilirubin levels, which are causal for hypertension in African-ancestry individuals

Serum bilirubin is associated with several clinical outcomes, including hypertension, type 2 diabetes (T2D), and drug metabolism. Here, we describe findings from our genome-wide association studies (GWAS) of serum (TBIL) using a generalized linear mixed model in West Africans (n = 1127), with adjustment for age, sex, body mass index, T2D, significant principal components of population structure, and cryptic relatedness. Genome-wide conditional analysis and CAVIARBF were used to fine map significant loci. The causal effect of TBIL on hypertension was assessed by Mendelian randomization (MR) using the GWAS findings as instrumental variables (IVs) in African Americans (n = 3,067). The SNP rs887829 (UGT1A1) was significantly associated with TBIL levels (effect allele (T) frequency = 0.49, β (SE) = 0.59 (0.04), p = 9.13 × 10−54). Genome-wide conditional analysis and regional fine mapping pointed to rs887829 as a possible causal variant with a posterior inclusion probability of 0.99. The T allele of rs887829 is associated with lower hepatic expression of UGT1A1. Using rs887829 as an IV, two-stage least-squares MR showed a causal effect of bilirubin on hypertension (β = −0.76, 95% CI [−1.52, −0.01], p = 0.0459). Our finding confirms that UGT1A1 influences bilirubin levels. Notably, lower TBIL is causally associated with the increased risk of hypertension.

Powers in Contemporary Philosophy

Four metaphysicians, Charlie Martin, David Lewis, David Armstrong, and George Molnar, offer distinctive approaches to understanding powers. Martin challenges the widely held view that disposition statements can be eliminated in favor of conditional statements. The apparent failure of the conditional analysis clears the path for Martin’s idea that all properties have some degree of irreducible dispositionality. Lewis takes on Martin’s challenge and offers his reformed conditional analysis. This analysis does not purport to eliminate talk of dispositions, but instead metaphysically reduces dispositions to their causal bases. Armstrong also reduces dispositions, but he reduces them to categorical universals governed by natural laws. Molnar argues that each of the aforementioned views falters when confronted with the powers of fundamental particles, which are said to be ungrounded pure powers. Molnar holds that both fundamental and derivative powers exist alongside non-power spatial and temporal properties. Debates among these four philosophers in the latter half of the 20th century constitute a substantial part of the reemergence of discussion of powers in contemporary metaphysics.

Arg206Cys substitution in DNASE1L3 causes a defect in DNASE1L3 protein secretion that confers risk of systemic lupus erythematosus

ObjectivesTo determine if the polymorphism encoding the Arg206Cys substitution in DNASE1L3 explains the association of the DNASE1L3/PXK gene locus with systemic lupus erythematosus (SLE) and to examine the effect of the Arg206Cys sequence change on DNASE1L3 protein function.MethodsConditional analysis for rs35677470 was performed on cases and controls with European ancestry from the SLE Immunochip study, and genotype and haplotype frequencies were compared. DNASE1L3 protein levels were measured in cells and supernatants of HEK293 cells and monocyte-derived dendritic cells expressing recombinant and endogenous 206Arg and 206Cys protein variants.ResultsConditional analysis on rs35677470 eliminated the SLE risk association signal for lead single-nucleotide polymorphisms (SNPs) rs180977001 and rs73081554, which are found to tag the same risk haplotype as rs35677470. The modest effect sizes of the SLE risk genotypes (heterozygous risk OR=1.14 and homozygous risk allele OR=1.68) suggest some DNASE1L3 endonuclease enzyme function is retained. An SLE protective signal in PXK (lead SNP rs11130643) remained following conditioning on rs35677470. The DNASE1L3 206Cys risk variant maintained enzymatic activity, but secretion of the artificial and endogenous DNASE1L3 206Cys protein was substantially reduced.ConclusionsSLE risk association in the DNASE1L3 locus is dependent on the missense SNP rs35677470, which confers a reduction in DNASE1L3 protein secretion but does not eliminate its DNase enzyme function.

LRP1 polymorphisms associated with warfarin stable dose in Chinese patients: a stepwise conditional analysis

Aim: The aim of this study was to investigate whether variability in warfarin stable dose (WSD) could be influenced by vitamin K-related polymorphisms in patients with heart valve replacement. Patients & methods: Twenty-nine vitamin K-related SNPs in 208 patients who initially took warfarin and achieved WSD were genotyped. Results: After conducting conditional analysis for both VKORC1 -1639G>A and CYP2C9*3, LRP1 rs1800139 and LRP1 rs1800154 were significantly associated with WSD (p = 0.007 and p = 0.015, respectively). Multivariate analysis showed that LRP1 rs1800139 accounted for 5.9% WSD variability. Conclusion: Our results suggest that a novel vitamin K-related gene, LRP1, exerts a relevant influence on WSD, independent of VKORC1 -1639G>A and CYP2C9*3.

Comparing Forward Conditional Analysis and Forward Logistic Regression Methods in a Landslide Susceptibility Assessment: A Case Study in Sicily

Forward logistic regression and conditional analysis have been compared to assess landslide susceptibility across the whole territory of the Sicilian region (about 25,000 km2) using previously existing data and a nested tiered approach. These approaches were aimed at singling out a statistical correlation between the spatial distribution of landslides that have affected the Sicilian region in the past, and a set of controlling factors: outcropping lithology, rainfall, landform classification, soil use, and steepness. The landslide inventory used the proposal of building the models like the official one obtained in the PAI (hydro geologic asset plan) project, amounting to more than 33,000 events. The 11 types featured in PAI were grouped into 4 macro-typologies, depending on the inherent conditions believed to generate various kinds of failures and their kinematic evolution. The study has confirmed that it is possible to carry out a regional landslide susceptibility assessment based solely on existing data (i.e., factor maps and the landslide archive), saving a considerable amount of time and money. For scarp landslides, where the selected factors (steepness, landform classification, and lithology) are more discriminate, models show excellent performance: areas under receiver operating characteristic (ROC) (AUCs) average > 0.9, while hillslope landslide results are highly satisfactory (average AUCs of about 0.8). The stochastic approach makes it possible to classify the Sicilian territory depending on its propensity to landslides in order to identify those municipalities which are most susceptible at this level of study, and are potentially worthy of more specific studies, as required by European-level protocols.