A Viewpoint on Population Analyses

Population analyses have become an indispensable tool to computational chemists. Yet implementation within popular quantum chemistry software has buried the interesting philosophical choices made when partitioning the electron density into atomic contributions. There is further historical context that has significantly influenced common conceptions of chemical bonding and reactivity. This work reviews select aspects of orbital and spatial decomposition schemes of the density matrix, pointing out essential linear algebraic considerations and associated tools of shared interest to us and Prof. Mayer.

Improving structural variant clustering to reduce the negative effect of the breakpoint uncertainty problem

Background Structural variants (SVs) represent an important source of genetic variation. One of the most critical problems in their detection is breakpoint uncertainty associated with the inability to determine their exact genomic position. Breakpoint uncertainty is a characteristic issue of structural variants detected via short-read sequencing methods and complicates subsequent population analyses. The commonly used heuristic strategy reduces this issue by clustering/merging nearby structural variants of the same type before the data from individual samples are merged. Results We compared the two most used dissimilarity measures for SV clustering in terms of Mendelian inheritance errors (MIE), kinship prediction, and deviation from Hardy–Weinberg equilibrium. We analyzed the occurrence of Mendelian-inconsistent SV clusters that can be collapsed into one Mendelian-consistent SV as a new measure of dataset consistency. We also developed a new method based on constrained clustering that explicitly identifies these types of clusters. Conclusions We found that the dissimilarity measure based on the distance between SVs breakpoints produces slightly better results than the measure based on SVs overlap. This difference is evident in trivial and corrected clustering strategy, but not in constrained clustering strategy. However, constrained clustering strategy provided the best results in all aspects, regardless of the dissimilarity measure used.

Incipient diploidization of the medicinal plant Perilla within 10,000 years

Perilla is a young allotetraploid Lamiaceae species widely used in East Asia as herb and oil plant. Here, we report the high-quality, chromosome-scale genomes of the tetraploid (Perilla frutescens) and the AA diploid progenitor (Perilla citriodora). Comparative analyses suggest post Neolithic allotetraploidization within 10,000 years, and nucleotide mutation in tetraploid is 10% more than in diploid, both of which are dominated by G:C → A:T transitions. Incipient diploidization is characterized by balanced swaps of homeologous segments, and subsequent homeologous exchanges are enriched towards telomeres, with excess of replacements of AA genes by fractionated BB homeologs. Population analyses suggest that the crispa lines are close to the nascent tetraploid, and involvement of acyl-CoA: lysophosphatidylcholine acyltransferase gene for high α-linolenic acid content of seed oil is revealed by GWAS. These resources and findings provide insights into incipient diploidization and basis for breeding improvement of this medicinal plant.

Molecular Characterization of Genetic Diversity in Apricot Cultivars: Current Situation and Future Perspectives

In the recent years, an important renewal of apricot cultivars is taking place worldwide with the introduction of a large number of new releases, which are replacing traditional and local cultivars in many situations. To study the current genetic diversity, a group of 202 apricot accessions, including landraces and releases from breeding programs in several countries, has been characterized using 13 microsatellite markers. The diversity parameters showed higher diversity in modern releases than in landraces, but also suggested a loss of diversity associated with recent breeding. Two main clusters according to the pedigree origin of the accessions were clearly differentiated in the phylogenetic analysis based on Nei’s genetic distance. The first group comprised mostly European and North American traditional cultivars, and the second group included the majority of recent and commercial releases from breeding programs. Further population analyses showed the same clustering trend on the distribution of individuals and clusters, confirming the results obtained in the molecular phylogenetic analysis. These results provide a sight of the erosion and the decrease of the genetic diversity in the currently grown apricot and highlight the importance of preserve traditional cultivars and local germplasm to assure genetic resources for further breeding.

No Time Dependence of Ciprofloxacin Pharmacokinetics in Critically Ill Adults: Comparison of Individual and Population Analyses

The aim of this prospective PK study was to evaluate the pharmacokinetics of ciprofloxacin dosed within the first 36 h (early phase) and after 3 days of treatment (delayed phase) using individual and population PK analysis. The secondary aim of the study was to evaluate possible dosing implications of the observed PK differences between early and delayed phases to achieve a PK/PD target for ciprofloxacin of AUC24/MIC ≥ 125. Blood concentrations of ciprofloxacin (1 and 4 h after dose and trough) were monitored in critically ill adults in the early and delayed phases of the treatment. Individual and population PK analyses were performed. Complete concentration-time profiles in the early phase, delayed phase, and both phases were obtained from 29, 15, and 14 patients, respectively. No systematic changes in ciprofloxacin PK parameters between the early and delayed phases were observed, although variability was higher at the early phase. Both individual and population analyses provided similar results. Simulations showed that after standard dosing, it is practically impossible to reach the recommended ciprofloxacin PK/PD target (AUC/MIC ≥ 125) for pathogens with MIC ≥ 0.5 mg/L. A dosing nomogram utilizing patients’ creatinine clearance and MIC values was constructed. Both individual and population analyses provided similar results. Therapeutic drug monitoring should be implemented to safeguard the optimal ciprofloxacin exposure.

A DFT Study on the Interaction of Doped Carbon Nanotubes with H2S, SO2 and Thiophene

The interactions of simple and Al-, B-, N-, S-, P-, and Si-doped carbon nanotubes with three sulfur-containing molecules (H2S, SO2, and thiophene) were investigated to assess their adsorption potencies and sensor abilities. The DFT method was used to calculate the adsorption energies and natural bond orbitals parameters. In addition, population analyses were performed to calculate the energy gaps and reactivity parameters. The results showed an exothermic interaction of H2S, SO2, and thiophene with simple and doped carbon nanotubes, while the maximum negative adsorption energies belong to Al- and B-containing complexes. Furthermore, evaluation of second-order perturbation energies (obtained from natural bond orbitals calculations) confirmed that the highest energies were related to B- and Al-containing intramolecular interactions. The results revealed the favorability of adsorption of SO2 by nanotubes (B- and Al-doped carbon nanotubes, in particular) compared with the other examined adsorbates.

Separating parental and treatment contributions to perinatal health after fresh and frozen embryo transfer in assisted reproduction: A cohort study with within-sibship analysis

Background Compared to naturally conceived children, adverse perinatal outcomes are more common among children born after assisted reproductive technology with fresh embryo transfer (fresh-ET) or frozen embryo transfer (frozen-ET). However, most previous studies could not adequately control for family confounding factors such as subfertility. We compared birth size and duration of pregnancy among infants born after fresh-ET or frozen-ET versus natural conception, using a within-sibship design to account for confounding by maternal factors. Methods and findings This registry-based cohort study with nationwide data from Denmark (1994–2014), Norway (1988–2015), and Sweden (1988–2015) consisted of 4,510,790 live-born singletons, 4,414,703 from natural conception, 78,095 from fresh-ET, and 17,990 from frozen-ET. We identified 33,056 offspring sibling groups with the same mother, conceived by at least 2 different conception methods. Outcomes were mean birthweight, small and large for gestational age, mean gestational age, preterm (<37 weeks, versus ≥37), and very preterm birth (<32 weeks, versus ≥32). Singletons born after fresh-ET had lower mean birthweight (−51 g, 95% CI −58 to −45, p < 0.001) and increased odds of small for gestational age (odds ratio [OR] 1.20, 95% CI 1.08 to 1.34, p < 0.001), while those born after frozen-ET had higher mean birthweight (82 g, 95% CI 70 to 94, p < 0.001) and increased odds of large for gestational age (OR 1.84, 95% CI 1.56 to 2.17, p < 0.001), compared to naturally conceived siblings. Conventional population analyses gave similar results. Compared to naturally conceived siblings, mean gestational age was lower after fresh-ET (−1.0 days, 95% CI −1.2 to −0.8, p < 0.001), but not after frozen-ET (0.3 days, 95% CI 0.0 to 0.6, p = 0.028). There were increased odds of preterm birth after fresh-ET (OR 1.27, 95% CI 1.17 to 1.37, p < 0.001), and in most models after frozen-ET, versus naturally conceived siblings, with somewhat stronger associations in population analyses. For very preterm birth, population analyses showed increased odds for both fresh-ET (OR 2.03, 95% CI 1.90 to 2.12, p < 0.001) and frozen-ET (OR 1.66, 95% CI 1.42 to 1.94, p < 0.001) compared with natural conception, but results were notably attenuated within siblings (OR 1.18, 95% CI 1.0 to 1.41, p = 0.059, and OR 0.92, 95% CI 0.67 to 1.27, p = 0.6, for fresh-ET and frozen-ET, respectively). Sensitivity analyses in full siblings, in siblings born within 3-year interval, by birth order, and restricting to single embryo transfers and blastocyst transfers were consistent with the main analyses. Main limitations were high proportions of missing data on maternal body mass index and smoking. Conclusions We found that infants conceived by fresh-ET had lower birthweight and increased odds of small for gestational age, and those conceived by frozen-ET had higher birthweight and increased odds of large for gestational age. Conception by either fresh-ET or frozen-ET was associated with increased odds of preterm birth. That these findings were observed within siblings, as well as in conventional multivariable population analyses, reduces the likelihood that they are explained by confounding or selection bias. Trial registration ClinicalTrials.gov ISRCTN11780826.

Replication of Quasi-Experimental Population Studies: Motivation and Guidance

Most quasi-experimental empirical analyses in accounting involve determining a set of sample selection criteria and then applying these criteria to obtain an exhaustive sample for analysis. By including all available observations, one might reasonably view such analyses as population studies. In this paper, I propose a structure and provide related interpretive guidance for conducting intentional, focused replications of population analyses defined by such sample selection criteria.