A study in scarlet: MC1R as the main predictor of red hair and exemplar of the flip-flop effect.

Genetic variation in melanocortin-1 receptor (MC1R) is a known contributor to disease-free red hair in humans. Three loss-of-function single-nucleotide variants (rs1805007, rs1805008 and rs1805009) have been established as strongly correlated with red hair. The contribution of other loss-of-function MC1R variants (in particular rs1805005, rs2228479 and rs885479) and the extent to which other genetic loci are involved in red hair colour is less well understood. Here, we used the UK Biobank cohort to capture a comprehensive list of MC1R variants contributing to red hair colour. We report a correlation with red hair for both strong-effect variants (rs1805007, rs1805008 and rs1805009) and weak-effect variants (rs1805005, rs2228479 and rs885479) and show that their coefficients differ by two orders of magnitude. On the haplotype level, both strong- and weak-effect variants contribute to the red hair phenotype, but when considered individually, weak-effect variants show a reverse, negative association with red hair. The reversal of association direction in the single-variant analysis is facilitated by a distinguishing structure of MC1R, in which loss-of-function variants are never found to co-occur on the same haplotype. The other previously reported hair colour genes' variants do not substantially improve the MC1R red hair colour predictive model. Our best model for predicting red versus other hair colours yields an unparalleled area under the receiver operating characteristic of 0.96 using only MC1R variants. In summary, we present a comprehensive statistically derived characterization of the role of MC1R variants in red hair colour and offer a powerful, economical and parsimonious model that achieves unsurpassed performance.

Clinical predictors of persistent temporomandibular disorder in people with first-onset temporomandibular disorder: A prospective case-control study.

BACKGROUND: When patients first develop a painful temporomandibular disorder (TMD) and seek care, 1 priority for clinicians is to assess prognosis. The authors aimed to develop a predictive model by using biopsychosocial measures from the Diagnostic Criteria for Temporomandibular Disorders (DC-TMD) to predict risk of developing TMD symptom persistence. METHODS: At baseline, trained examiners identified 260 participants with first-onset TMD classified by using DC-TMD-compliant protocols. After follow-up at least 6 months later, 72 (49%) had examiner-classified TMD (persistent cases), and 75 (51%) no longer had examiner-classified TMD (transient cases). For multivariable logistic regression analysis, the authors used blocks of variables selected using minimum redundancy maximum relevance to construct a model to predict the odds of TMD persistence. RESULTS: At onset, persistent cases had multiple worse TMD clinical measures and, among Axis II measures, only greater baseline pain intensity (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.04 to 2.2; P = .030) and more physical symptoms (OR, 1.8; 95% CI, 1.2 to 2.9; P = .004) than did transient cases. A multivariable model using TMD clinical measures showed greater discriminative capacity (area under the receiver operating characteristic curve, 0.74; 95% CI, 0.73 to 0.75) than did a model involving psychosocial measures (area under the receiver operating characteristic curve, 0.63; 95% CI, 0.62 to 0.64). CONCLUSIONS: Clinical measures that clinicians can assess readily when TMD first develops are useful in predicting the risk of developing persistent TMD. Psychosocial measures are important predictors of onset but do not add meaningfully to the predictive capacity of clinical measures. PRACTICAL IMPLICATIONS: When TMD first develops, clinicians usefully can identify patients at higher risk of developing persistence by using clinical measures that they logically also could use in treatment planning and for monitoring outcomes of intervention.

Human pain genetics database: a resource dedicated to human pain genetics research.

The Human Pain Genetics Database (HPGDB) is a comprehensive variant-focused inventory of genetic contributors to human pain. After curation, the HPGDB currently includes 294 studies reporting associations between 434 distinct genetic variants and various pain phenotypes. Variants were then submitted to a comprehensive analysis. First, they were validated in an independent high-powered replication cohort by testing the association of each variant with 10 different pain phenotypes (n = 1320-26,973). One hundred fifty-five variants replicated successfully (false discovery rate 20%) in at least one pain phenotype, and the association P values of the HPGDB variants were significantly lower compared with those of random controls. Among the 155 replicated variants, 21 had been included in the HPGDB because of their association with analgesia-related and 13 with nociception-related phenotypes, confirming analgesia and nociception as pathways of vulnerability for pain phenotypes. Furthermore, many genetic variants were associated with multiple pain phenotypes, and the strength of their association correlated between many pairs of phenotypes. These genetic variants explained a considerable amount of the variance between different pairs of pain phenotypes, indicating a shared genetic basis among pain phenotypes. In addition, we found that HPGDB variants show many pleiotropic associations, indicating that genetic pathophysiological mechanisms are also shared among painful and nonpainful conditions. Finally, we demonstrated that the HPGDB data set is significantly enriched for functional variants that modify gene expression, are deleterious, and colocalize with open chromatin regions. As such, the HPGDB provides a validated data set that represents a valuable resource for researchers in the human pain field.

Vertex collocation profiles: theory, computation, and results.

We describe the vertex collocation profile (VCP) concept. VCPs provide rich information about the surrounding local structure of embedded vertex pairs. VCP analysis offers a new tool for researchers and domain experts to understand the underlying growth mechanisms in their networks and to analyze link formation mechanisms in the appropriate sociological, biological, physical, or other context. The same resolution that gives the VCP method its analytical power also enables it to perform well when used to accomplish link prediction. We first develop the theory, mathematics, and algorithms underlying VCPs. We provide timing results to demonstrate that the algorithms scale well even for large networks. Then we demonstrate VCP methods performing link prediction competitively with unsupervised and supervised methods across different network families. Unlike many analytical tools, VCPs inherently generalize to multirelational data, which provides them with unique power in complex modeling tasks. To demonstrate this, we apply the VCP method to longitudinal networks by encoding temporally resolved information into different relations. In this way, the transitions between VCP elements represent temporal evolutionary patterns in the longitudinal network data. Results show that VCPs can use this additional data, typically challenging to employ, to improve predictive model accuracies. We conclude with our perspectives on the VCP method and its future in network science, particularly link prediction.

Range-limited centrality measures in complex networks.

Here we present a range-limited approach to centrality measures in both nonweighted and weighted directed complex networks. We introduce an efficient method that generates for every node and every edge its betweenness centrality based on shortest paths of lengths not longer than ℓ=1,...,L in the case of nonweighted networks, and for weighted networks the corresponding quantities based on minimum weight paths with path weights not larger than w(ℓ)=ℓΔ, ℓ=1,2...,L=R/Δ. These measures provide a systematic description on the positioning importance of a node (edge) with respect to its network neighborhoods one step out, two steps out, etc., up to and including the whole network. They are more informative than traditional centrality measures, as network transport typically happens on all length scales, from transport to nearest neighbors to the farthest reaches of the network. We show that range-limited centralities obey universal scaling laws for large nonweighted networks. As the computation of traditional centrality measures is costly, this scaling behavior can be exploited to efficiently estimate centralities of nodes and edges for all ranges, including the traditional ones. The scaling behavior can also be exploited to show that the ranking top list of nodes (edges) based on their range-limited centralities quickly freezes as a function of the range, and hence the diameter-range top list can be efficiently predicted. We also show how to estimate the typical largest node-to-node distance for a network of N nodes, exploiting the afore-mentioned scaling behavior. These observations were made on model networks and on a large social network inferred from cell-phone trace logs (∼5.5×10(6) nodes and ∼2.7×10(7) edges). Finally, we apply these concepts to efficiently detect the vulnerability backbone of a network (defined as the smallest percolating cluster of the highest betweenness nodes and edges) and illustrate the importance of weight-based centrality measures in weighted networks in detecting such backbones.