Mikkel Meyer Andersen

Y-STR Frequency Surveying Method: A critical reappraisal

Reasonable formalized methods to estimate the frequencies of DNA profiles generated from lineage markers have been proposed in the past years and were discussed in the forensic community. Recently, collections of population data on the frequencies of variations in Y chromosomal STR profiles have reached a new quality with the establishment of the comprehensive neatly quality-controlled reference database YHRD. Grounded on such unrivalled empirical material from hundreds of populations studies the core assumption of the Haplotype Frequency Surveying Method originally described 10 years ago can be tested and improved. Here we provide new approaches to calculate the parameters used in the frequency surveying method: a maximum likelihood estimation of the regression parameters (r(1), r(2), s(1) and s(2)) and a revised Frequency Surveying framework with variable binning and a database preprocessing to take the population sub-structure into account. We found good estimates for 11 metapopulations using both approaches and demonstrate that the statistical basis of the method is well supported and independent of the population under study. The results of the estimation process are reliable and robust if the underlying datasets are large and representative and show small average and pairwise genetic distances.

The effect of gender on eye colour variation in European populations and an evaluation of the IrisPlex prediction model

In two recent studies of Spanish individuals, gender was suggested as a factor that contributes to human eye colour variation. However, gender did not improve the predictive accuracy on blue, intermediate and brown eye colours when gender was included in the IrisPlex model. In this study, we investigate the role of gender as a factor that contributes to eye colour variation and suggest that the gender effect on eye colour is population specific. A total of 230 Italian individuals were typed for the six IrisPlex SNPs (rs12913832, rs1800407, rs12896399, rs1393350, rs16891982 and rs12203592). A quantitative eye colour score (Pixel Index of the Eye: PIE-score) was calculated based on digital eye images using the custom made DIAT software. The results were compared with those of Danish and Swedish population samples. As expected, we found HERC2 rs12913832 as the main predictor of human eye colour independently of ancestry. Furthermore, we found gender to be significantly associated with quantitative eye colour measurements in the Italian population sample. We found that the association was statistically significant only among Italian individuals typed as heterozygote GA for HERC2 rs12913832. Interestingly, we did not observe the same association in the Danish and Swedish population. This indicated that the gender effect on eye colour is population specific. We estimated the effect of gender on quantitative eye colour in the Italian population sample to be 4.9%. Among gender and the IrisPlex SNPs, gender ranked as the second most important predictor of human eye colour variation in Italians after HERC2 rs12913832. We, furthermore, tested the five lower ranked IrisPlex predictors, and evaluated all possible 3(6) (729) genotype combinations of the IrisPlex assay and their corresponding predictive values using the IrisPlex prediction model [4]. The results suggested that maximum three (rs12913832, rs1800407, rs16891982) of the six IrisPlex SNPs are useful in practical forensic genetic casework.

Cluster analysis of European Y-chromosomal STR haplotypes using the discrete Laplace method

The European Y-chromosomal short tandem repeat (STR) haplotype distribution has previously been analysed in various ways. Here, we introduce a new way of analysing population substructure using a new method based on clustering within the discrete Laplace exponential family that models the probability distribution of the Y-STR haplotypes. Creating a consistent statistical model of the haplotypes enables us to perform a wide range of analyses. Previously, haplotype frequency estimation using the discrete Laplace method has been validated. In this paper we investigate how the discrete Laplace method can be used for cluster analysis to further validate the discrete Laplace method. A very important practical fact is that the calculations can be performed on a normal computer. We identified two sub-clusters of the Eastern and Western European Y-STR haplotypes similar to results of previous studies. We also compared pairwise distances (between geographically separated samples) with those obtained using the AMOVA method and found good agreement. Further analyses that are impossible with AMOVA were made using the discrete Laplace method: analysis of the homogeneity in two different ways and calculating marginal STR distributions. We found that the Y-STR haplotypes from e.g. Finland were relatively homogeneous as opposed to the relatively heterogeneous Y-STR haplotypes from e.g. Lublin, Eastern Poland and Berlin, Germany. We demonstrated that the observed distributions of alleles at each locus were similar to the expected ones. We also compared pairwise distances between geographically separated samples from Africa with those obtained using the AMOVA method and found good agreement.

How convincing is a matching Y-chromosome profile?

The introduction of forensic autosomal DNA profiles was controversial, but the problems were successfully addressed, and DNA profiling has gone on to revolutionise forensic science. Y-chromosome profiles are valuable when there is a mixture of male-source and female-source DNA, and interest centres on the identity of the male source(s) of the DNA. The problem of evaluating evidential weight is even more challenging for Y profiles than for autosomal profiles. Numerous approaches have been proposed, but they fail to deal adequately with the fact that men with matching Y-profiles are related in extended patrilineal clans, many of which may not be represented in available databases. The higher mutation rates of modern profiling kits have led to increased discriminatory power but they have also exacerbated the problem of fairly conveying evidential value. Because the relevant population is difficult to define, yet the number of matching relatives is fixed as population size varies, it is typically infeasible to derive population-based match probabilities relevant to a specific crime. We propose a conceptually simple solution, based on a simulation model and software to approximate the distribution of the number of males with a matching Y profile. We show that this distribution is robust to different values for the variance in reproductive success and the population growth rate. We also use importance sampling reweighting to derive the distribution of the number of matching males conditional on a database frequency, finding that this conditioning typically has only a modest impact. We illustrate the use of our approach to quantify the value of Y profile evidence for a court in a way that is both scientifically valid and easily comprehensible by a judge or juror.

Nonoperative treatment improves pain irrespective of radiographic severity. A cohort study of 1,414 patients with knee osteoarthritis.

Background and purpose — The discrepancy between symptoms and radiographic severity of knee osteoarthritis (OA) is well described. However, little is known about whether radiographic severity is predictive of the clinical result of nonoperative treatment. We investigated whether radiographic severity and treatment type were associated with improvements in pain after nonoperative treatment of patients with knee OA. Patients and methods — A 5-year consecutive series of patients deemed not eligible for total knee arthroplasty (TKA) by an experienced orthopedic surgeon was contacted 1–5 years later. Radiographic severity, age, sex, and BMI were registered at the consultation. At follow-up, patients were asked to answer a questionnaire on type of treatment and improvements in pain after treatment. Results — Of 1,848 patients who were not eligible for TKA, 1,414 (77%) completed the follow-up questionnaire (mean age 66 (24–96) years; 55% women). Radiographic severity was not associated with improvements in pain even after adjusting for treatment type, age, sex, and BMI (p > 0.1). The odds ratio of improvement was higher by a factor of 2 in patients who received physiotherapy or multimodal treatment than in patients who did not. Interpretation — Radiographic severity was not associated with improvements in pain after nonoperative treatment. Patients who are not eligible for TKA can confidently be referred to nonoperative treatment even if they have severe radiographic OA. The treatment should preferably be multimodal, including physiotherapy, as recommended in Danish and international clinical guidelines.

Importance of nonsynonymous OCA2 variants in human eye color prediction

The color of the eyes is one of the most prominent phenotypes in humans and it is often used to describe the appearance of an individual. The intensity of pigmentation in the iris is strongly associated with one single‐nucleotide polymorphism (SNP), rs12913832:A>G that is located in the promotor region of OCA2 (OMIM #611409). Nevertheless, many eye colors cannot be explained by only considering rs12913832:A>G.

malan: MAle Lineage ANalysis

The problem of evaluating evidential weight is even more challenging for Y-profiles than for autosomal profiles that are based on the non-sex chromosomes. At the core of the weight of evidence for autosomal short tandem repeat (STR) profiles used in forensic genetics is the match probability, which is the conditional probability that a particular individual X has a matching profile, given that the queried contributor, Q, has it (Steele and Balding 2015). Matching at a single, autosomal STR allele is relatively common: typically a few percent of individuals from the same population share a given allele. The probability of matching is increased when X is a relative of Q, but for typical population sizes most of the individuals sharing a given allele are not closely related to Q.

Discrete Laplace mixture model with applications in forensic genetics

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Mechanical axis of the lower extremity determined by a new digital photographic method

Assessment of the mechanical axis is routine during the examination of patients with lower extremity pain. Long-leg radiographic examination is the gold standard for exact measurement, but it is associated with a significant radiation dose. An alternative method to examine the mechanical axis has been warranted. This article validates a newly developed computerized photograph method to calculate the mechanical axis using a digital photograph. The location of the center of the femoral head was calculated using ink marks on both superior iliac spines. Twenty-five patients (10 women and 15 men) had both legs examined using the photographic method and long-leg radiography examination. The digital photograph method was found to be highly reliable. The interobserver absolute mean difference was 0.99°±0.85°, and the intraobserver absolute mean difference (day-to-day variation) was 1.04°±0.81°. The mechanical axis determined by the 2 methods was highly correlated (R=0.943). The long-leg radiography method was within an average of ±1.88° of the photographic method, with a 95% probability. The photographic method appears to be an effective alternative to conventional long-leg radiography. The photographic method seems convenient in the routine examination of patients with leg pain and children with suspected axial deformity and for follow-up after treatment for malalignment. Calculation coefficients for children and a possible racial difference remain to be studied.

Y-profile evidence: Close paternal relatives and mixtures

We recently introduced a new approach to the evaluation of weight of evidence (WoE) for Y-chromosome profiles. Rather than attempting to calculate match probabilities, which is particularly problematic for modern Y-profiles with high mutation rates, we proposed using simulation to describe the distribution of the number of males in the population with a matching Y-profile, both the unconditional distribution and conditional on a database frequency of the profile. Here we further validate the new approach by showing that our results are robust to assumptions about the allelic ladder and the founder haplotypes, and we extend the approach in two important directions. Firstly, forensic databases are not the only source of background data relevant to the evaluation of Y-profile evidence: in many cases the Y-profiles of one or more relatives of the accused are also available. To date it has been unclear how to use this additional information, but in our simulation-based approach its effect is readily incorporated. We describe this approach and illustrate how the WoE that a man was the source of an observed Y-profile changes when the Y-profiles of some of his male-line relatives are also available. Secondly, we extend our new approach to mixtures of Y-profiles from two or more males. Surprisingly, our simulation-based approach reveals that observing a 2-male mixture that includes an alleged contributors profile is almost as strong evidence as observing a matching single-contributor evidence sample, and even 3-male and 4-male mixtures are only slightly weaker.