Evaluation of DNA Mixtures from Database Search

Summary .  With the aim of bridging the gap between DNA mixture analysis and DNA database search, a novel approach is proposed to evaluate the forensic evidence of DNA mixtures when the suspect is identified by the search of a database of DNA profiles. General formulae are developed for the calculation of the likelihood ratio for a two-person mixture under general situations including multiple matches and imperfect evidence. The influence of the prior probabilities on the weight of evidence under the scenario of multiple matches is demonstrated by a numerical example based on Hong Kong data. Our approach is shown to be capable of presenting the forensic evidence of DNA mixtures in a comprehensive way when the suspect is identified through database search.     

The effect of relatedness on likelihood ratios and the use of conservative estimates

DNA profiling can be used to identify criminals through their DNA matching that left at the scene of a crime. The strength of the evidence supplied by a match in DNA profiles is given by the likelihood ratio. This, in turn, depends upon the probability that a match would be produced if the suspect is innocent. This probability could be strongly affected by the possibility of relatedness between the suspect and the true source of the scene-of-crime DNA profile. Methods are shown that allow for the possibility of such relatedness, arising either through population substructure or through a family relationship. Uncertainties about the likelihood ratio have been taken as grounds for the use of very conservative estimates of this quantity. The use of such conservative estimates can be shown to be neither necessary nor harmless.Editor's commentsThe author makes a good case for the use of likelihood ratios in presenting evidence. The author cites Nichols and Balding (1991) for the match probability involvingF _ST , and readers will also need to consult Balding and Nichols (1994 and this volume) and Weir (1994). In light of current concern over laboratory errors or fraud, the author's comment that Undetected and unsuspected human error or mischief is potentially a problem in almost all criminal cases, yet no convictions could follow if this possibility was consistently deemed to lead to reasonable doubt is well taken.     

Conditional genotypic probabilities for microsatellite loci

Modern forensic DNA profiles are constructed using microsatellites, short tandem repeats of 2-5 bases. In the absence of genetic data on a crime-specific subpopulation, one tool for evaluating profile evidence is the match probability. The match probability is the conditional probability that a random person would have the profile of interest given that the suspect has it and that these people are different members of the same subpopulation. One issue in evaluating the match probability is population differentiation, which can induce coancestry among subpopulation members. Forensic assessments that ignore coancestry typically overstate the strength of evidence against the suspect. Theory has been developed to account for coancestry; assumptions include a steady-state population and a mutation model in which the allelic state after a mutation event is independent of the prior state. Under these assumptions, the joint allelic probabilities within a subpopulation may be approximated by the moments of a Dirichlet distribution. We investigate the adequacy of this approximation for profiled loci that mutate according to a generalized stepwise model. Simulations suggest that the Dirichlet theory can still overstate the evidence against a suspect with a common microsatellite genotype. However, Dirichlet-based estimators were less biased than the product-rule estimator, which ignores coancestry.     

Stress,Uncertainty and Decision Confidence

We successfully manipulated decision confidence in a probabilistic prediction task by means of stress as induced by excessive cognitive demands. In particular, our results indicate that decisions (based on high and low, but not intermediate levels of uncertainty) made under stress (confirmed by skin conductance measures) are associated with increased confidence when outcome probabilities are incompletely known (20% residual uncertainty). A different pattern was found when outcome probabilities were completely known (0% residual uncertainty). Here, stress led to decreased decision confidence when decisions were associated with intermediate levels of uncertainty but had no effect in case of high and low levels of uncertainty. In addition we provide evidence for ambiguity—(understood as implicit-risk) assessment being impaired under stress conditions.     

Match probabilities in a finite, subdivided population

We generalize a recently introduced graphical framework to compute the probability that haplotypes or genotypes of two individuals drawn from a finite, subdivided population match. As in the previous work, we assume an infinite-alleles model. We focus on the case of a population divided into two subpopulations, but the underlying framework can be applied to a general model of population subdivision. We examine the effect of population subdivision on the match probabilities and the accuracy of the product rule which approximates multi-locus match probabilities as a product of one-locus match probabilities. We quantify the deviation from predictions of the product rule by R, the ratio of the multi-locus match probability to the product of the one-locus match probabilities. We carry out the computation for two loci and find that ignoring subdivision can lead to underestimation of the match probabilities if the population under consideration actually has subdivision structure and the individuals originate from the same subpopulation. On the other hand, under a given model of population subdivision, we find that the ratio R for two loci is only slightly greater than 1 for a large range of symmetric and asymmetric migration rates. Keeping in mind that the infinite-alleles model is not the appropriate mutation model for STR loci, we conclude that, for two loci and biologically reasonable parameter values, population subdivision may lead to results that disfavor innocent suspects because of an increase in identity-by-descent in finite populations. On the other hand, for the same range of parameters, population subdivision does not lead to a substantial increase in linkage disequilibrium between loci. Those results are consistent with established practice.     

Mother's curse: the effect of mtDNA on individual fitness and population viability

The mitochondrial genome is considered generally to be an innocent bystander in adaptive evolution; however, there is increasing evidence that mitochondrial DNA (mtDNA) is an important contributor to viability and fecundity. Some of this evidence is now well documented, with mtDNA mutations having been shown to play a causal role in degenerative diseases, ageing, and cancer. However, most research on mtDNA has ignored the possibility that other instances exist where mtDNA mutations could have profound fitness consequences. Recent work in humans and other species now indicates that mtDNA mutations play an important role in sperm function, male fertility, and male fitness. Ironically, deleterious mtDNA mutations that affect only males, such as those that impair sperm function, will not be subject to natural selection because mitochondria are generally maternally inherited and could reach high frequencies in populations if the mutations are not disadvantageous in females. Here, we review how such mtDNA mutations might affect the viability of natural populations. We consider factors that increase or decrease the strength of the effect of mtDNA mutations on population viability and discuss what mechanisms exist to mitigate deleterious mtDNA effects.     

Detection and Integration of Genotyping Errors in Statistical Genetics

Detection of genotyping errors and integration of such errors in statistical analysis are relatively neglected topics, given their importance in gene mapping. A few inopportunely placed errors, if ignored, can tremendously affect evidence for linkage. The present study takes a fresh look at the calculation of pedigree likelihoods in the presence of genotyping error. To accommodate genotyping error, we present extensions to the Lander-Green-Kruglyak deterministic algorithm for small pedigrees and to the Markov-chain Monte Carlo stochastic algorithm for large pedigrees. These extensions can accommodate a variety of error models and refrain from simplifying assumptions, such as allowing, at most, one error per pedigree. In principle, almost any statistical genetic analysis can be performed taking errors into account, without actually correcting or deleting suspect genotypes. Three examples illustrate the possibilities. These examples make use of the full pedigree data, multiple linked markers, and a prior error model. The first example is the estimation of genotyping error rates from pedigree data. The second-and currently most useful-example is the computation of posterior mistyping probabilities. These probabilities cover both Mendelian-consistent and Mendelian-inconsistent errors. The third example is the selection of the true pedigree structure connecting a group of people from among several competing pedigree structures. Paternity testing and twin zygosity testing are typical applications.     

Silent witness, articulate collective: DNA evidence and the inference of visible traits

DNA profiling is a well-established technology for use in the criminal justice system, both in courtrooms and elsewhere. The fact that DNA profiles are based on non-coding DNA and do not reveal details about the physical appearance of an individual has contributed to the acceptability of this type of evidence. Its success in criminal investigation, combined with major innovations in the field of genetics, have contributed to a change of role for this type of evidence. Nowadays DNA evidence is not merely about identification, where trace evidence is compared to a sample taken from a suspect. An ever-growing role is anticipated for DNA profiling as an investigative tool, a technique aimed at generating a suspect where there is none. One of these applications is the inference of visible traits. As this article will show, racial classifications are at the heart of this application. The Netherlands and its legal regulation of 'externally visible traits' will serve as an example. It will be shown that, to make this technology work, a large number of actors has to be enrolled and their articulations invited. This indicates that instead of a 'silent witness', a DNA profile should rather be seen as an 'articulate collective'. Based on two cases, I argue that the normativity of visible traits is context-dependent. Taking into account the practices in which technology is put to use alerts us to novel ethical questions raised by their application.     

A method for characterizing transition concertedness from polymer dynamics computer simulations

A statistical method based on classifying the transitions among a set of dihedral angles within an “energy transfer window” is developed, and used to analyze Brownian (BD) and molecular dynamics (MD) simulations of the acyl chains in a lipid bilayer, and MD of neat hexadecane. It is shown for the BD simulation that when a transition of the dihedral angle in the center of the chain occurs, a transition of a particular next nearest neighbor (or angle 2-apart) will follow concertedly with a probability of approximately 0.10 within a lime window of approximately 3 ps. The MD bilayer simulations, which are based on a more flexible model of the hydrocarbon chains, yield corresponding concerted transition probabilities of approximately 0.083 and window sizes of 1–2 ps. An analysis of angles 4-apart yields concerted transition probabilities of 0.03 and 0.04 for the BD and MD bilayer simulations, respectively, and window sizes close to those of the corresponding 2-apart cases. Statistical hypothesis testing very strongly rejects the assertion that these follower transitions are occurring at random. Similar analysis reveals marginal or no evidence of concertedness between 1-apart (nearest neighbor) and between 3-apart dihedral angle transitions. The pattern of concertedness for hexadecane is qualitatively similar to that of the lipid chains, although concertedness is somewhat stronger for the 3-apart transitions and somewhat weaker for those 4-apart. Finally, it is suggested that the diffusion of small solute molecules in membranes is better facilitated by non concerted transitions, which are associated with relatively large displacements of the chains, than by concerted transitions, which do little to change the chain shape. © 1995 John Wiley & Sons, Inc.     

Serotonin transporter genotype (5-HTTLPR) predicts utilitarian moral judgments

Background

The psychological and neurobiological processes underlying moral judgment have been the focus of extensive recent research. Here we show that serotonin transporter (5-HTTLPR) genotype predicts responses to moral dilemmas featuring foreseen harm to an innocent.

Methodology/Principal Findings

Participants in this study judged the acceptability of actions that would unintentionally or intentionally harm an innocent victim in order to save others'' lives. An analysis of variance revealed a genotype × scenario interaction, F(2, 63) = 4.52, p = .02. Results showed that, relative to long allele homozygotes (LL), carriers of the short (S) allele showed particular reluctance to endorse utilitarian actions resulting in foreseen harm to an innocent individual. LL genotype participants rated perpetrating unintentional harm as more acceptable (M = 4.98, SEM = 0.20) than did SL genotype participants (M = 4.65, SEM = 0.20) or SS genotype participants (M = 4.29, SEM = 0.30). No group differences in moral judgments were observed in response to scenarios featuring intentional harm.

Conclusions/Significance

The results indicate that inherited variants in a genetic polymorphism that influences serotonin neurotransmission influence utilitarian moral judgments as well. This finding is interpreted in light of evidence that the S allele is associated with elevated emotional responsiveness.     

The DNA database search controversy revisited: bridging the Bayesian-frequentist gap

Two different quantities have been suggested for quantification of evidence in cases where a suspect is found by a search through a database of DNA profiles. The likelihood ratio, typically motivated from a Bayesian setting, is preferred by most experts in the field. The so-called np rule has been suggested through frequentist arguments and has been suggested by the American National Research Council and Stockmarr (1999, Biometrics55, 671-677). The two quantities differ substantially and have given rise to the DNA database search controversy. Although several authors have criticized the different approaches, a full explanation of why these differences appear is still lacking. In this article we show that a P-value in a frequentist hypothesis setting is approximately equal to the result of the np rule. We argue, however, that a more reasonable procedure in this case is to use conditional testing, in which case a P-value directly related to posterior probabilities and the likelihood ratio is obtained. This way of viewing the problem bridges the gap between the Bayesian and frequentist approaches. At the same time it indicates that the np rule should not be used to quantify evidence.     

Enthalpies of transfer for proteins from aqueous to water-alcohol solutions: a test for models of residues exposed to solvent

The enthalpies of transfer of proteins from aqueous solution to alcohol–water solutions are used as probes of solvent-accessible surface for these proteins. Enthalpies of transfer to 10 wt% ethanol solutions are determined calorimetrically for the native proteins ribonuclease A, lysozyme, and ovalbumin. Ribonuclease A and lysozyme are reduced and carboxamidomethylated to produce configurations in which interior residues of the native protein are exposed to the solvent; enthalpies of transfer are determined for these species. These data are then compared with enthalpies of transfer for the constituent amino acids of the proteins. The enthalpies of transfer for the residues are used to generate a maximal enthalpy of transfer that can be compared with the enthalpies of transfer for the reduced, carboxamidomethylated proteins. The residue amino acid enthalpies are coupled with probabilities that each residue is an exterior residue to predict an enthalpy of transfer for the native protein that can be compared with the observed enthalpy. The probabilities developed by Wertz and Scheraga and Lee and Richards, and Chothia are then compared on their ability to predict the native enthalpies of transfer for the protein. The Wertz–Scheraga model gives the better fit of this data in all cases.     

Cells of the synovium in rheumatoid arthritis. Synovial fibroblasts

For some time synovial fibroblasts have been regarded simply as innocent synovial cells, mainly responsible for synovial homeostasis. During the past decade, however, a body of evidence has accumulated illustrating that rheumatoid arthritis synovial fibroblasts (RASFs) are active drivers of joint destruction in rheumatoid arthritis. Details regarding the intracellular signalling cascades that result in long-term activation and synthesis of proinflammatory molecules and matrix-degrading enzymes by RASFs have been analyzed. Molecular, cellular and animal studies have identified various interactions with other synovial and inflammatory cells. This expanded knowledge of the distinct role played by RASFs in the pathophysiology of rheumatoid arthritis has moved these fascinating cells to the fore, and work to identify targeted therapies to inhibit their joint destructive potential is underway.     

Genetic analysis by chromosome-mediated gene transfer.

A general method is presented for stable transfer of genetic information to eukaryotic cells, utilizing metaphase chromosomes as the vehicle. Recent progress, current problems and large areas of uncertainty in this field are reviewed; particular consideration is given to frequency of transfer, size of the transgenome, evidence of cotransfer of linked genes and serial chromosome transfer. A reasonable model for chromosome transfer is considered with respect to the available information, and various descrepancies are noted. The utility of this method for fine structural mapping, cloning small regions of the eukaryotic genome and other potential applications are discussed.     

Classifying microRNAs in cancer: the good, the bad and the ugly

MicroRNAs (miRNAs) have quite recently emerged as a novel class of gene regulators. Many miRNAs exhibit altered expression levels in cancer, and we are only starting to understand the functional consequences of the loss or gain of particular miRNAs to the cancerous phenotype. miRNAs can be classified with regard to their role in cancer as the Good, the Bad and the Ugly. The "Good", those miRNAs that are innocent bystanders in the oncogenic transformation process, whose expression profile might even be used for cancer diagnosis or prognosis. The "Bad", those miRNAs that are causally linked to tumorigenesis and directly modify tumor suppressor- or oncogenic- pathways. And the "Ugly", those miRNAs whose inappropriate loss or gain destabilizes the cellular identity of a tumor, which indirectly results in enhanced phenotypic variability and progression of the tumor. Hereunder we will discuss the possible ways in which miRNAs can be relevant to cancer biology, and possible experimental strategies for elucidating the mechanisms involved.     

Application of radiationless energy transfer for distance measurements across membranes

For several 2- or 3-dimensional configurations of stationary donors and acceptors on or near a spherical membrane shell the transition probabilities for radiationless energy transfer are calculated, using Förster's approximation obtained for Coulombic dipole-dipole interaction of the transition moments. It turns out that the difference in the refractive indices for membrane (lipid) and bulk phase (water) has only a small influence on the transition probabilities. Furthermore, the curvature of biological cell surfaces can be neglected, but affects the energy transfer across small vesicles. The ratio thickness/radius of small vesicles can be determined by measuring fluorescence quenching of excited donors by acceptors on the other side of the membrane.     

Premelting thermal fluctuational interbase hydrogen-bond disrupted states of a B-DNA guanine-cytosine base pair: significance for amino and imino proton exchange.

Modified self-consistent phonon theory when applied to the DNA double helix indicates the existence of fairly long-lived states in which single interbase H bonds are disrupted. One can then postulate a number of situations in which particular disrupted H bonds can enhance particular proton exchange. In this paper we postulate a number of such partially open states for a B-conformation GC base pair and calculate the probability of each of these states for a B-conformation poly(dG).poly(dC). We compare these probabilities to those probabilities needed to explain various observed proton exchange rates. We propose that, for a GC base pair in B conformation, there are two amino proton exchangeable states--a cytosine amino proton exchangeable state and a guanine amino proton exchangeable state; both require the disruption of only the corresponding interbase H bond. The imino proton exchange, however, requires the disruption of all three interbase H bonds and this defines a third open state. Our calculated probabilities for a GC base pair in these three states are in fair agreement with available experimental estimates from measurements of amino and imino proton exchange.     

Using parametric multipoint lods and mods for linkage analysis requires a shift in statistical thinking

Multipoint (MP) linkage analysis represents a valuable tool for whole-genome studies but suffers from the disadvantage that its probability distribution is unknown and varies as a function of marker information and density, genetic model, number and structure of pedigrees, and the affection status distribution [Xing and Elston: Genet Epidemiol 2006;30:447-458; Hodge et al.: Genet Epidemiol 2008;32:800-815]. This implies that the MP significance criterion can differ for each marker and each dataset, and this fact makes planning and evaluation of MP linkage studies difficult. One way to circumvent this difficulty is to use simulations or permutation testing. Another approach is to use an alternative statistical paradigm to assess the statistical evidence for linkage, one that does not require computation of a p value. Here we show how to use the evidential statistical paradigm for planning, conducting, and interpreting MP linkage studies when the disease model is known (lod analysis) or unknown (mod analysis). As a key feature, the evidential paradigm decouples uncertainty (i.e. error probabilities) from statistical evidence. In the planning stage, the user calculates error probabilities, as functions of one's design choices (sample size, choice of alternative hypothesis, choice of likelihood ratio (LR) criterion k) in order to ensure a reliable study design. In the data analysis stage one no longer pays attention to those error probabilities. In this stage, one calculates the LR for two simple hypotheses (i.e. trait locus is unlinked vs. trait locus is located at a particular position) as a function of the parameter of interest (position). The LR directly measures the strength of evidence for linkage in a given data set and remains completely divorced from the error probabilities calculated in the planning stage. An important consequence of this procedure is that one can use the same criterion k for all analyses. This contrasts with the situation described above, in which the value one uses to conclude significance may differ for each marker and each dataset in order to accommodate a fixed test size, α. In this study we accomplish two goals that lead to a general algorithm for conducting evidential MP linkage studies. (1) We provide two theoretical results that translate into guidelines for investigators conducting evidential MP linkage: (a) Comparing mods to lods, error rates (including probabilities of weak evidence) are generally higher for mods when the null hypothesis is true, but lower for mods in the presence of true linkage. Royall [J Am Stat Assoc 2000;95:760-780] has shown that errors based on lods are bounded and generally small. Therefore when the true disease model is unknown and one chooses to use mods, one needs to control misleading evidence rates only under the null hypothesis; (b) for any given pair of contiguous marker loci, error rates under the null are greatest at the midpoint between the markers spaced furthest apart, which provides an obvious simple alternative hypothesis to specify for planning MP linkage studies. (2) We demonstrate through extensive simulation that this evidential approach can yield low error rates under the null and alternative hypotheses for both lods and mods, despite the fact that mod scores are not true LRs. Using these results we provide a coherent approach to implement a MP linkage study using the evidential paradigm.     

Constraining prior probabilities of phylogenetic trees

Although Bayesian methods are widely used in phylogenetic systematics today, the foundations of this methodology are still debated among both biologists and philosophers. The Bayesian approach to phylogenetic inference requires the assignment of prior probabilities to phylogenetic trees. As in other applications of Bayesian epistemology, the question of whether there is an objective way to assign these prior probabilities is a contested issue. This paper discusses the strategy of constraining the prior probabilities of phylogenetic trees by means of the Principal Principle. In particular, I discuss a proposal due to Velasco (Biol Philos 23:455–473, 2008) of assigning prior probabilities to tree topologies based on the Yule process. By invoking the Principal Principle I argue that prior probabilities of tree topologies should rather be assigned a weighted mixture of probability distributions based on Pinelis’ (P Roy Soc Lond B Bio 270:1425–1431, 2003) multi-rate branching process including both the Yule distribution and the uniform distribution. However, I argue that this solves the problem of the priors of phylogenetic trees only in a weak form.