Focus: A Multifaceted Battle Against Cancer: Extracting Knowledge from Chemical Imaging Data Using Computational Algorithms for Digital Cancer Diagnosis

Fourier transform infrared (FTIR) spectroscopic imaging is an emerging microscopy modality for clinical histopathologic diagnoses as well as for biomedical research. Spectral data recorded in this modality are indicative of the underlying, spatially resolved biochemical composition but need computerized algorithms to digitally recognize and transform this information to a diagnostic tool to identify cancer or other physiologic conditions. Statistical pattern recognition forms the backbone of these recognition protocols and can be used for highly accurate results. Aided by biochemical correlations with normal and diseased states and the power of modern computer-aided pattern recognition, this approach is capable of combating many standing questions of traditional histology-based diagnosis models. For example, a simple diagnostic test can be developed to determine cell types in tissue. As a more advanced application, IR spectral data can be integrated with patient information to predict risk of cancer, providing a potential road to precision medicine and personalized care in cancer treatment. The IR imaging approach can be implemented to complement conventional diagnoses, as the samples remain unperturbed and are not destroyed. Despite high potential and utility of this approach, clinical implementation has not yet been achieved due to practical hurdles like speed of data acquisition and lack of optimized computational procedures for extracting clinically actionable information rapidly. The latter problem has been addressed by developing highly efficient ways to process IR imaging data but remains one that has considerable scope for progress. Here, we summarize the major issues and provide practical considerations in implementing a modified Bayesian classification protocol for digital molecular pathology. We hope to familiarize readers with analysis methods in IR imaging data and enable researchers to develop methods that can lead to the use of this promising technique for digital diagnosis of cancer.     

Historical demographic profiles and genetic variation of the East African Butana and Kenana indigenous dairy zebu cattle

Butana and Kenana breeds from Sudan are part of the East African zebu Bos indicus type of cattle. Unlike other indigenous zebu cattle in Africa, they are unique due to their reputation for high milk production and are regarded as dairy cattle, the only ones of their kind on the African continent. In this study, we sequenced the complete mitochondrial DNA (mtDNA) D‐loop of 70 animals to understand the maternal genetic variation, demographic profiles and history of the two breeds in relation to the history of cattle pastoralism on the African continent. Only taurine mtDNA sequences were identified. We found very high mtDNA diversity but low level of maternal genetic structure within and between the two breeds. Bayesian coalescent‐based analysis revealed different historical and demographic profiles for the two breeds, with an earlier population expansion in the Butana vis a vis the Kenana. The maternal ancestral populations of the two breeds may have diverged prior to their introduction into the African continent, with first the arrival of the ancestral Butana population. We also reveal distinct demographic history between the two breeds with the Butana showing a decline in its effective population size (N_e) in the recent past ~590 years. Our results provide new insights on the early history of cattle pastoralism in Sudan indicative of a large ancient effective population size.     

Priors for the Bayesian star paradox

We show that the Bayesian star paradox, first proved mathematically by Steel and Matsen for a specific class of prior distributions, occurs in a wider context including less regular, possibly discontinuous, prior distributions.     

Spatial and temporal factors associated with nest survival of Gray Flycatchers in managed ponderosa pine forests

Gray Flycatchers (Empidonax wrightii) breed in a variety of habitats in the arid and semi‐arid regions of the western United States, but little is known about their breeding biology, especially in the northern portion of their range where they nest in ponderosa pine (Pinus ponderosa) forests. From May to July 2014 and 2015, we conducted surveys for singing male Gray Flycatchers along the eastern slope of the Cascade Range in Washington, U.S.A, monitored flycatcher nests, and quantified nest‐site vegetation. We used a logistic‐exposure model fit within a Bayesian framework to model the daily survival probability of flycatcher nests. During the 2 yr of our study, we monitored 141 nests, with 93% in ponderosa pines. Mean clutch size was 3.6 eggs and the mean number of young fledged per nest was 3.2. Predation accounted for 90% of failed nests. We found a positive association between daily nest survival and both nest height and distance of nest substrates from the nearest tree. Flycatchers that locate their nests higher above the ground and further from adjacent trees may be choosing the safest alternative because higher nests may be less exposed to terrestrial predators and nests in trees that are farther from other trees may be less exposed to arboreal predators such as jays (Corvidae) that may forage in patches with connected canopies. Nests in trees farther from other trees may also allow earlier detection of approaching predators and thus aid in nest defense.     

Exclosure fences around nests of imperiled Florida Grasshopper Sparrows reduce rates of predation by mammals

Increasing nest survival by excluding predators is a goal of many bird conservation programs. However, new exclosure projects should be carefully evaluated to assess the potential risks of disturbance. We tested the effectiveness of predator exclosure fences (hereafter, fences) for nests of critically endangered Florida Grasshopper Sparrows (Ammodramus savannarum floridanus) at a dry prairie site (Three Lakes; 2015–2018) and a pasture site (the Ranch; 2015–2016) in Osceola County, Florida, USA. We installed fences at nests an average of 8 days after the start of incubation, and nest abandonment after fence installation was rare (2 of 149 installations). Predation was the leading cause of failure for unfenced nests at both sites (48–73%). At Three Lakes, nest cameras revealed that mammals and snakes were responsible for 61.5% and 38.5% of predation events, respectively, at unfenced nests. Fences reduced the daily probability of predation (0.016 for fenced nests vs. 0.074 for unfenced nests). The probability that a fenced nest would survive from discovery to fledging was more than double that of unfenced nests (60.4% vs. 27.7%). However, we found no difference in daily nest survival at the Ranch between the year before nests were fenced (2015; 0.874) and the year when all but one nest were fenced (2016; 0.867) because red imported fire ants (Solenopsis invicta) were responsible for 86% of predation events at fenced nests at the Ranch. The use of cameras at fenced nests revealed that site‐specific differences in nest predators explained variation in fence efficiency between sites. Our fence design may be useful for other species of grassland birds, but site‐specific predator communities and species‐specific response of target bird species to fences should be assessed before installing fences at other sites.     

Extending phylogeography to account for lineage fusion

Secondary contact between long isolated populations has several possible outcomes. These include the strengthening of preexisting reproductive isolating mechanisms via reinforcement, the emergence of a hybrid lineage that is distinct from its extant parental lineages and which occupies a spatially restricted zone between them, or complete merging of two populations such that parental lineages are no longer extant (“lineage fusion” herein). The latter scenario has rarely been explicitly considered in single‐species and comparative phylogeographic studies, yet it has the potential to impact inferences about population history and levels of congruence. In this paper, we explore the idea that insights into past lineage fusion may now be possible, owing to the advent of next‐generation sequencing. Using simulated DNA sequence haplotype datasets (i.e., loci with alleles comprised of a set of linked nucleotide polymorphisms), we examined basic requirements (number of loci and individuals sampled) for identifying cases when a present‐day panmictic population is the product of lineage fusion, using an exemplar statistical framework—approximate Bayesian computation. We found that with approximately 100 phased haplotype loci (each 400 bp long) and modest sample sizes of individuals (10 per population), lineage fusion can be detected under rather challenging scenarios. This included some scenarios where reticulation was fully contained within a Last Glacial Maximum timeframe, provided that mixing was symmetrical, ancestral gene pools were moderately to deeply diverged, and the lag time between the fusion event and gene pool sampling was relatively short. However, the more realistic case of asymmetrical mixing is not prohibitive if additional genetic data (e.g., 400 loci) are available. Notwithstanding some simplifying assumptions of our simulations and the knowledge gaps that remain about the circumstances under which lineage fusion is potentially detectable, we suggest that the recent release from data limitation allows phylogeographers to expand the scope of inferences about long‐term population history.     

Bayesian Quantile Regression for Longitudinal Studies with Nonignorable Missing Data

Summary .  We study quantile regression (QR) for longitudinal measurements with nonignorable intermittent missing data and dropout. Compared to conventional mean regression, quantile regression can characterize the entire conditional distribution of the outcome variable, and is more robust to outliers and misspecification of the error distribution. We account for the within-subject correlation by introducing a   ℓ₂   penalty in the usual QR check function to shrink the subject-specific intercepts and slopes toward the common population values. The informative missing data are assumed to be related to the longitudinal outcome process through the shared latent random effects. We assess the performance of the proposed method using simulation studies, and illustrate it with data from a pediatric AIDS clinical trial.     

Plausibility of inferred ancestral phenotypes and the evaluation of alternative models of limb evolution in scincid lizards

Phylogenetic approaches to inferring ancestral character states are becoming increasingly sophisticated; however, the potential remains for available methods to yield strongly supported but inaccurate ancestral state estimates. The consistency of ancestral states inferred for two or more characters affords a useful criterion for evaluating ancestral trait reconstructions. Ancestral state estimates for multiple characters that entail plausible phenotypes when considered together may reasonably be assumed to be reliable. However, the accuracy of inferred ancestral states for one or more characters may be questionable where combined reconstructions imply implausible phenotypes for a proportion of internal nodes. This criterion for assessing reconstructed ancestral states is applied here in evaluating inferences of ancestral limb morphology in the scincid lizard clade Lerista. Ancestral numbers of digits for the manus and pes inferred assuming the models that best fit the data entail ancestral digit configurations for many nodes that differ fundamentally from configurations observed among known species. However, when an alternative model is assumed for the pes, inferred ancestral digit configurations are invariably represented among observed phenotypes. This indicates that a suboptimal model for the pes (and not the model providing the best fit to the data) yields accurate ancestral state estimates.