An Improved Fst Estimator

The fixation index F _st plays a central role in ecological and evolutionary genetic studies. The estimators of Wright (F^st1), Weir and Cockerham (F^st2), and Hudson et al. (F^st3) are widely used to measure genetic differences among different populations, but all have limitations. We propose a minimum variance estimator F^stm using F^st1 and F^st2. We tested F^stm in simulations and applied it to 120 unrelated East African individuals from Ethiopia and 11 subpopulations in HapMap 3 with 464,642 SNPs. Our simulation study showed that F^stm has smaller bias than F^st2 for small sample sizes and smaller bias than F^st1 for large sample sizes. Also, F^stm has smaller variance than F^st2 for small F _st values and smaller variance than F^st1 for large F _st values. We demonstrated that approximately 30 subpopulations and 30 individuals per subpopulation are required in order to accurately estimate F _st.     

Effects of Overlapping Generations on Linkage Disequilibrium Estimates of Effective Population Size

Use of single-sample genetic methods to estimate effective population size has skyrocketed in recent years. Although the underlying models assume discrete generations, they are widely applied to age-structured species. We simulated genetic data for 21 iteroparous animal and plant species to evaluate two untested hypotheses regarding performance of the single-sample method based on linkage disequilibrium (LD): (1) estimates based on single-cohort samples reflect the effective number of breeders in one reproductive cycle (N_b), and (2) mixed-age samples reflect the effective size per generation (N_e). We calculated true N_e and N_b, using the model species’ vital rates, and verified these with individual-based simulations. We show that single-cohort samples should be equally influenced by N_b and N_e and confirm this with simulated results: N^b was a linear (r² = 0.98) function of the harmonic mean of N_e and N_b. We provide a quantitative bias correction for raw N^b based on the ratio N_b/N_e, which can be estimated from two or three simple life history traits. Bias-adjusted estimates were within 5% of true N_b for all 21 study species and proved robust when challenged with new data. Mixed-age adult samples produced downwardly biased estimates in all species, which we attribute to a two-locus Wahlund effect (mixture LD) caused by combining parents from different cohorts in a single sample. Results from this study will facilitate interpretation of rapidly accumulating genetic estimates in terms of both N_e (which influences long-term evolutionary processes) and N_b (which is more important for understanding eco-evolutionary dynamics and mating systems).     

A Novel Approach for Choosing Summary Statistics in Approximate Bayesian Computation

The choice of summary statistics is a crucial step in approximate Bayesian computation (ABC). Since statistics are often not sufficient, this choice involves a trade-off between loss of information and reduction of dimensionality. The latter may increase the efficiency of ABC. Here, we propose an approach for choosing summary statistics based on boosting, a technique from the machine-learning literature. We consider different types of boosting and compare them to partial least-squares regression as an alternative. To mitigate the lack of sufficiency, we also propose an approach for choosing summary statistics locally, in the putative neighborhood of the true parameter value. We study a demographic model motivated by the reintroduction of Alpine ibex (Capra ibex) into the Swiss Alps. The parameters of interest are the mean and standard deviation across microsatellites of the scaled ancestral mutation rate (θ_anc = 4N_eu) and the proportion of males obtaining access to matings per breeding season (ω). By simulation, we assess the properties of the posterior distribution obtained with the various methods. According to our criteria, ABC with summary statistics chosen locally via boosting with the L₂-loss performs best. Applying that method to the ibex data, we estimate θ^anc≈1.288 and find that most of the variation across loci of the ancestral mutation rate u is between 7.7 × 10⁻⁴ and 3.5 × 10⁻³ per locus per generation. The proportion of males with access to matings is estimated as ω^≈0.21, which is in good agreement with recent independent estimates.     

The Impact of Prior Information on Estimates of Disease Transmissibility Using Bayesian Tools

The basic reproductive number (R₀) and the distribution of the serial interval (SI) are often used to quantify transmission during an infectious disease outbreak. In this paper, we present estimates of R₀ and SI from the 2003 SARS outbreak in Hong Kong and Singapore, and the 2009 pandemic influenza A(H1N1) outbreak in South Africa using methods that expand upon an existing Bayesian framework. This expanded framework allows for the incorporation of additional information, such as contact tracing or household data, through prior distributions. The results for the R₀ and the SI from the influenza outbreak in South Africa were similar regardless of the prior information (R^0 = 1.36–1.46, μ^ = 2.0–2.7, μ^ = mean of the SI). The estimates of R₀ and μ for the SARS outbreak ranged from 2.0–4.4 and 7.4–11.3, respectively, and were shown to vary depending on the use of contact tracing data. The impact of the contact tracing data was likely due to the small number of SARS cases relative to the size of the contact tracing sample.     

Rhinos in the Parks: An Island-Wide Survey of the Last Wild Population of the Sumatran Rhinoceros

In the 200 years since the Sumatran rhinoceros was first scientifically described (Fisher 1814), the range of the species has contracted from a broad region in Southeast Asia to three areas on the island of Sumatra and one in Kalimantan, Indonesia. Assessing population and spatial distribution of this very rare species is challenging because of their elusiveness and very low population number. Using an occupancy model with spatial dependency, we assessed the fraction of the total landscape occupied by Sumatran rhinos over a 30,345-km² survey area and the effects of covariates in the areas where they are known to occur. In the Leuser Landscape (surveyed in 2007), the model averaging result of conditional occupancy estimate was ψ^(SE[ψ^])=0.151(0.109) or 2,371.47 km², and the model averaging result of replicated level detection probability p^(SE[p^])=0.252(0.267); in Way Kambas National Park—2008: ψ^(SE[ψ^])=0.468(0.165) or 634.18 km², and p^(SE[p^])=0.138(0.571); and in Bukit Barisan Selatan National Park—2010: ψ^(SE[ψ^])=0.322(0.049) or 819.67 km², and p^(SE[p^])=0.365(0.42). In the Leuser Landscape, rhino occurrence was positively associated with primary dry land forest and rivers, and negatively associated with the presence of a road. In Way Kambas, occurrence was negatively associated with the presence of a road. In Bukit Barisan Selatan, occurrence was negatively associated with presence of primary dryland forest and rivers. Using the probabilities of site occupancy, we developed spatially explicit maps that can be used to outline intensive protection zones for in-situ conservation efforts, and provide a detailed assessment of conserving Sumatran rhinos in the wild. We summarize our core recommendation in four points: consolidate small population, strong protection, determine the percentage of breeding females, and recognize the cost of doing nothing. To reduce the probability of poaching, here we present only the randomized location of site level occupancy in our result while retaining the overall estimation of occupancy for a given area.     

A Variable Sampling Interval Synthetic Xbar Chart for the Process Mean

The usual practice of using a control chart to monitor a process is to take samples from the process with fixed sampling interval (FSI). In this paper, a synthetic X¯ control chart with the variable sampling interval (VSI) feature is proposed for monitoring changes in the process mean. The VSI synthetic X¯ chart integrates the VSI X¯ chart and the VSI conforming run length (CRL) chart. The proposed VSI synthetic X¯ chart is evaluated using the average time to signal (ATS) criterion. The optimal charting parameters of the proposed chart are obtained by minimizing the out-of-control ATS for a desired shift. Comparisons between the VSI synthetic X¯ chart and the existing X¯, synthetic X¯, VSI X¯ and EWMA X¯ charts, in terms of ATS, are made. The ATS results show that the VSI synthetic X¯ chart outperforms the other X¯ type charts for detecting moderate and large shifts. An illustrative example is also presented to explain the application of the VSI synthetic X¯ chart.     

A Bayesian method for identifying associations between response variables and bacterial community composition

Determining associations between intestinal bacteria and continuously measured physiological outcomes is important for understanding the bacteria-host relationship but is not straightforward since abundance data (compositional data) are not normally distributed. To address this issue, we developed a fully Bayesian linear regression model (BRACoD; Bayesian Regression Analysis of Compositional Data) with physiological measurements (continuous data) as a function of a matrix of relative bacterial abundances. Bacteria can be classified as operational taxonomic units or by taxonomy (genus, family, etc.). Bacteria associated with the physiological measurement were identified using a Bayesian variable selection method: Stochastic Search Variable Selection. The output is a list of inclusion probabilities (p^) and coefficients that indicate the strength of the association (β^included) for each bacterial taxa. Tests with simulated communities showed that adopting a cut point value of p^ ≥ 0.3 for identifying included bacteria optimized the true positive rate (TPR) while maintaining a false positive rate (FPR) of ≤ 5%. At this point, the chances of identifying non-contributing bacteria were low and all well-established contributors were included. Comparison with other methods showed that BRACoD (at p^ ≥ 0.3) had higher precision and a higher TPR than a commonly used center log transformed LASSO procedure (clr-LASSO) as well as higher TPR than an off-the-shelf Spike and Slab method after center log transformation (clr-SS). BRACoD was also less likely to include non-contributing bacteria that merely correlate with contributing bacteria. Analysis of a rat microbiome experiment identified 47 operational taxonomic units that contributed to fecal butyrate levels. Of these, 31 were positively and 16 negatively associated with butyrate. Consistent with their known role in butyrate metabolism, most of these fell within the Lachnospiraceae and Ruminococcaceae. We conclude that BRACoD provides a more precise and accurate method for determining bacteria associated with a continuous physiological outcome compared to clr-LASSO. It is more sensitive than a generalized clr-SS algorithm, although it has a higher FPR. Its ability to distinguish genuine contributors from correlated bacteria makes it better suited to discriminating bacteria that directly contribute to an outcome. The algorithm corrects for the distortions arising from compositional data making it appropriate for analysis of microbiome data.     

Influence of Adjuvant Therapy in Cancer Survivors on Endothelial Function and Skeletal Muscle Deoxygenation

The cardiotoxic effects of adjuvant cancer treatments (i.e., chemotherapy and radiation treatment) have been well documented, but the effects on peripheral cardiovascular function are still unclear. We hypothesized that cancer survivors i) would have decreased resting endothelial function; and ii) altered muscle deoxygenation response during moderate intensity cycling exercise compared to cancer-free controls. A total of 8 cancer survivors (~70 months post-treatment) and 9 healthy controls completed a brachial artery FMD test, an index of endothelial-dependent dilation, followed by an incremental exercise test up to the ventilatory threshold (VT) on a cycle ergometer during which pulmonary V˙O2 and changes in near-infrared spectroscopy (NIRS)-derived microvascular tissue oxygenation (TOI), total hemoglobin concentration ([Hb]_total), and muscle deoxygenation ([HHb] ≈ fractional O₂ extraction) were measured. There were no significant differences in age, height, weight, and resting blood pressure between cancer survivors and control participants. Brachial artery FMD was similar between groups (P = 0.98). During exercise at the VT, TOI was similar between groups, but [Hb]_total and [HHb] were significantly decreased in cancer survivors compared to controls (P < 0.01) The rate of change for TOI (ΔTOIΔ/V˙O2) and [HHb] (Δ[HHb]/ΔV˙O2) relative to ΔV˙O2 were decreased in cancer survivors compared to controls (P = 0.02 and P = 0.03 respectively). In cancer survivors, a decreased skeletal muscle microvascular function was observed during moderate intensity cycling exercise. These data suggest that adjuvant cancer therapies have an effect on the integrated relationship between O₂ extraction, V˙O2 and O₂ delivery during exercise.     

Pedigree analysis of the Turkish Arab horse population: structure,inbreeding and genetic variability

The aim of this study was to evaluate genetic variability in the Turkish Arab horse population using pedigree information. This study is the first detailed pedigree analysis of the breed in Turkey. Pedigree data were collected from the National Studbook. The pedigree data for 23 668 horses, born between 1904 and 2014, were used in the analysis. From this data set, a reference population (RP) of 14 838 animals symbolising the last generation was defined. Demographic parameters, the inbreeding level (F), the average relatedness (AR), the effective population size (N_e), the effective number of founders (f_e), the effective number of ancestors (f_a) and the number of founder genome equivalents (f_g) were calculated for the population. The average generation interval for the RP was 12.2±4.6 years, whereas the calculated pedigree completeness levels were 98.2%, 96.6% and 95.0% for the first, second and third known generations. The mean equivalent generations (t), the average complete generations and the mean maximum generations for the RP were 7.8, 5.4 and 12.2, respectively, whereas the meanFand AR were 4.6% and 9.5% for the RP. The rate of inbred animals was 94.2% for the RP, whereas the number of founders, the number of ancestors and thef_e,f_aandf_gwere 342, 223, 40, 22 and 9.6 for the RP. The large differences observed betweenf_e, and the number of founders demonstrates that genetic diversity decreased between the founder and the RP. Contribution of the 14 most influential founder to the RP was 50.0%, whereas just eight ancestral horses can account for 50% of the genetic variability.N_eestimated via an individual increase in inbreeding per generation (${\overline{N}}_{\text{e}}$), and paired increase in coancestry$\left(\text{}{\overline{N}}_{eC}\right)$, were 74.4±3.9 and 73.5±0.58, respectively. The inbreeding increases with the pedigree knowledge. In addition, the decrease in inbreeding in last years is more noticeable.     

Correlation of a Decline in Aerobic Capacity with Development of Emphysema in Patients with Chronic Obstructive Pulmonary Disease: A Prospective Observational Study

In patients with COPD, CT assessment of emphysema and airway disease is known to be associated with lung function and 6-minute walk distance. However, it remains to be determined whether low attenuation area (LAA) on CT is associated with aerobic capacity assessed using cardiopulmonary exercise testing (CPET). In this prospective observational study, we repeatedly conducted high-resolution CT and CPET using a treadmill in 81 COPD patients over a median interval of 3.5 years. Two investigators independently scored LAA on images obtained at the aortic arch level, tracheal bifurcation level, and supradiaphragmatic level. Grades for the images of each lung were added to yield the total LAA score. Total LAA score was negatively correlated with peak aerobic capacity (V˙O2) (p<0.001, r = -0.485). LAA scores of the upper (aortic arch level) and the lower (supradiaphragmatic level) lungs were both significantly associated with peak V˙O2. There was a significant correlation between total LAA score and peak CO₂ output (V˙CO2) (p<0.001, r = -0.433). Total LAA score was correlated with oxygen saturation at peak exercise (p<0.001, r = -0.634) and the estimated dead space fraction (p<0.001, r = 0.416). The mean annual change in total LAA score was significantly correlated with those in peak V˙O2 (p<0.001, r = -0.546) and peak V˙CO2 (p<0.001, r = -0.488). The extent of emphysema measured by CT was associated with the results of CPET. The time-dependent changes in CPET data were also correlated with that in total LAA score. CT assessment could be a non-invasive tool to predict aerobic capacity in patients with COPD.     

A Novel Method for Quantifying the Inhaled Dose of Air Pollutants Based on Heart Rate,Breathing Rate and Forced Vital Capacity

To better understand the interaction of physical activity and air pollution exposure, it is important to quantify the change in ventilation rate incurred by activity. In this paper, we describe a method for estimating ventilation using easily-measured variables such as heart rate (HR), breathing rate (f_B), and forced vital capacity (FVC). We recruited healthy adolescents to use a treadmill while we continuously measured HR, f_B, and the tidal volume (V_T) of each breath. Participants began at rest then walked and ran at increasing speed until HR was 160–180 beats per minute followed by a cool down period. The novel feature of this method is that minute ventilation (V˙E) was normalized by FVC. We used general linear mixed models with a random effect for subject and identified nine potential predictor variables that influence either V˙E or FVC. We assessed predictive performance with a five-fold cross-validation procedure. We used a brute force selection process to identify the best performing models based on cross-validation percent error, the Akaike Information Criterion and the p-value of parameter estimates. We found a two-predictor model including HR and f_B to have the best predictive performance (V˙E/FVC = -4.247+0.0595HR+0.226f_B, mean percent error = 8.1±29%); however, given the ubiquity of HR measurements, a one-predictor model including HR may also be useful (V˙E/FVC = -3.859+0.101HR, mean percent error = 11.3±36%).     

Prediction of risk of prolonged post-concussion symptoms: Derivation and validation of the TRICORDRR (Toronto Rehabilitation Institute Concussion Outcome Determination and Rehab Recommendations) score

BackgroundApproximately 10% to 20% of people with concussion experience prolonged post-concussion symptoms (PPCS). There is limited information identifying risk factors for PPCS in adult populations. This study aimed to derive a risk score for PPCS by determining which demographic factors, premorbid health conditions, and healthcare utilization patterns are associated with need for prolonged concussion care among a large cohort of adults with concussion.Methods and findingsData from a cohort study (Ontario Concussion Cohort study, 2008 to 2016; n = 1,330,336) including all adults with a concussion diagnosis by either primary care physician (ICD-9 code 850) or in emergency department (ICD-10 code S06) and 2 years of healthcare tracking postinjury (2008 to 2014, n = 587,057) were used in a retrospective analysis. Approximately 42.4% of the cohort was female, and adults between 18 and 30 years was the largest age group (31.0%). PPCS was defined as 2 or more specialist visits for concussion-related symptoms more than 6 months after injury index date. Approximately 13% (73,122) of the cohort had PPCS. Total cohort was divided into Derivation (2009 to 2013, n = 417,335) and Validation cohorts (2009 and 2014, n = 169,722) based upon injury index year. Variables selected a priori such as psychiatric disorders, migraines, sleep disorders, demographic factors, and pre-injury healthcare patterns were entered into multivariable logistic regression and CART modeling in the Derivation Cohort to calculate PPCS estimates and forward selection logistic regression model in the Validation Cohort. Variables with the highest probability of PPCS derived in the Derivation Cohort were: Age >61 years (p^ = 0.54), bipolar disorder (p^ = 0.52), high pre-injury primary care visits per year (p^ = 0.46), personality disorders (p^ = 0.45), and anxiety and depression (p^ = 0.33). The area under the curve (AUC) was 0.79 for the derivation model, 0.79 for bootstrap internal validation of the Derivation Cohort, and 0.64 for the Validation model. A limitation of this study was ability to track healthcare usage only to healthcare providers that submit to Ontario Health Insurance Plan (OHIP); thus, some patients seeking treatment for prolonged symptoms may not be captured in this analysis.ConclusionsIn this study, we observed that premorbid psychiatric conditions, pre-injury health system usage, and older age were associated with increased risk of a prolonged recovery from concussion. This risk score allows clinicians to calculate an individual’s risk of requiring treatment more than 6 months post-concussion.

In a retrospective study of data from a cohort of adults with a concussion diagnosis in Ontario, Laura Kathleen Langer and colleagues derive a risk score for predicting risk of prolonged post-concussion symptoms.     

Physicochemical Properties and Amino Acid Composition of Alkaline Proteinase from Aspergillus sojae

Some physicochemical properties and amino acid composition of alkaline proteinase from Aspergillus sojae were found to be as follows: The isoelectric point was at pH 5.1. The molecular weight was 25,500 using the Sheraga-Mandelkern’s formula, based upon the values of the sedimentation coefficient $(s_{20,w}^{°}=\text{?}2.82\text{?}\text{S})$, the intrinsic viscosity ([η] = 0.027 dl/g), and the partial specific volume $({\displaystyle \overline{V}}\text{?}=\text{?}0.726\text{?}\text{ml}/\text{g})$. The enzyme contains 16.8% of nitrogen and is composed of 250 residues of amino acid; Asp₃₁ Glu₁₉, Gly₂₇, Ala₃₂, Val₁₈, Leu₁₄, Ile₁₄, Ser₂₈, Thr₁₈, ${\text{(}{\displaystyle \stackrel{}{{\displaystyle \stackrel{?}{\text{Cys C}}}}}\text{ys})}_1$, Met₂, Pro₆, Phe₇, Tyr₈, Trp₂, His₅, Lys₁₄, Arg₃, (amide-NH₃)₂₀.     

A Comparison of the Structure of Curdlan and Pachyman

The fine structure of curdlan produced by Alcaligenes faecalis var. myxogenes 10C3, mutant K, and pachyman from Poria cocos were investigated, with regard to their gel-forming properties. Periodate oxidation showed that both polysaccharides contain very high proportions of (1→3)-linked glucose residues. On complete hydrolysis the glucan polyalcohol obtained by periodate oxidation and borohydride reduction of curdlan (${\displaystyle \overline{\text{DP}}}$ 455) gave glucose and glycerol, in the molar ratio of 125~130: 1, and on mild acid hydrolysis yielded degraded polysaccharide (${\displaystyle \overline{\text{DP}}}$ 155), confirming the previous conclusion that curdlan has an essentially unbranched structure though it may contain a few internal (1→6)-glucosidic linkages. On complete hydrolysis the glucan polyalcohol derived from pachyman (${\displaystyle \overline{\text{DP}}}$ 255) gave glucose and glycerol, in the ratio of 40:1, and on mild hydrolysis it yielded degraded polysaccharide (${\displaystyle \overline{\text{DP}}}$ 130). This indicates that pachyman contains on the average four branch points and one internal (1→6)-glucosidic linkage in the molecule.