Issues in Reproducible Simulation Research.

In recent years, serious concerns have arisen about reproducibility in science. Estimates of the cost of irreproducible preclinical studies range from 28 billion USD per year in the USA alone (Freedman et al. in PLoS Biol 13(6):e1002165, 2015) to over 200 billion USD per year worldwide (Chalmers and Glasziou in Lancet 374:86-89, 2009). The situation in the social sciences is not very different: Reproducibility in psychological research, for example, has been estimated to be below 50% as well (Open Science Collaboration in Science 349:6251, 2015). Less well studied is the issue of reproducibility of simulation research. A few replication studies of agent-based models, however, suggest the problem for computational modeling may be more severe than for laboratory experiments (Willensky and Rand in JASSS 10(4):2, 2007; Donkin et al. in Environ Model Softw 92:142-151, 2017; Bajracharya and Duboz in: Proceedings of the symposium on theory of modeling and simulation-DEVS integrative M&S symposium, pp 6-11, 2013). In this perspective, we discuss problems of reproducibility in agent-based simulations of life and social science problems, drawing on best practices research in computer science and in wet-lab experiment design and execution to suggest some ways to improve simulation research practice.

Optimization and Control of Agent-Based Models in Biology: A Perspective.

Agent-based models (ABMs) have become an increasingly important mode of inquiry for the life sciences. They are particularly valuable for systems that are not understood well enough to build an equation-based model. These advantages, however, are counterbalanced by the difficulty of analyzing and using ABMs, due to the lack of the type of mathematical tools available for more traditional models, which leaves simulation as the primary approach. As models become large, simulation becomes challenging. This paper proposes a novel approach to two mathematical aspects of ABMs, optimization and control, and it presents a few first steps outlining how one might carry out this approach. Rather than viewing the ABM as a model, it is to be viewed as a surrogate for the actual system. For a given optimization or control problem (which may change over time), the surrogate system is modeled instead, using data from the ABM and a modeling framework for which ready-made mathematical tools exist, such as differential equations, or for which control strategies can explored more easily. Once the optimization problem is solved for the model of the surrogate, it is then lifted to the surrogate and tested. The final step is to lift the optimization solution from the surrogate system to the actual system. This program is illustrated with published work, using two relatively simple ABMs as a demonstration, Sugarscape and a consumer-resource ABM. Specific techniques discussed include dimension reduction and approximation of an ABM by difference equations as well systems of PDEs, related to certain specific control objectives. This demonstration illustrates the very challenging mathematical problems that need to be solved before this approach can be realistically applied to complex and large ABMs, current and future. The paper outlines a research program to address them.

Exercise training comprising of single 20-s cycle sprints does not provide a sufficient stimulus for improving maximal aerobic capacity in sedentary individuals.

PURPOSE: Sprint interval training (SIT) provides a potent stimulus for improving maximal aerobic capacity ([Formula: see text]), which is among the strongest markers for future cardiovascular health and premature mortality. Cycling-based SIT protocols involving six or more 'all-out' 30-s Wingate sprints per training session improve [Formula: see text], but we have recently demonstrated that similar improvements in [Formula: see text] can be achieved with as few as two 20-s sprints. This suggests that the volume of sprint exercise has limited influence on subsequent training adaptations. Therefore, the aim of the present study was to examine whether a single 20-s cycle sprint per training session can provide a sufficient stimulus for improving [Formula: see text]. METHODS: Thirty sedentary or recreationally active participants (10 men/20 women; mean ± SD age: 24 ± 6 years, BMI: 22.6 ± 4.0 kg m(-2), [Formula: see text]: 33 ± 7 mL kg(-1) min(-1)) were randomised to a training group or a no-intervention control group. Training involved three exercise sessions per week for 4 weeks, consisting of a single 20-s Wingate sprint (no warm-up or cool-down). [Formula: see text] was determined prior to training and 3 days following the final training session. RESULTS: Mean [Formula: see text] did not significantly change in the training group (2.15 ± 0.62 vs. 2.22 ± 0.64 L min(-1)) or the control group (2.07 ± 0.69 vs. 2.08 ± 0.68 L min(-1); effect of time: P = 0.17; group × time interaction effect: P = 0.26). CONCLUSION: Although we have previously demonstrated that regularly performing two repeated 20-s 'all-out' cycle sprints provides a sufficient training stimulus for a robust increase in [Formula: see text], our present study suggests that this is not the case when training sessions are limited to a single sprint.

Effects of a 12-month moderate weight loss intervention on insulin sensitivity and inflammation status in nondiabetic overweight and obese subjects.

Weight loss intervention is the principal non-pharmacological method for prevention and treatment of type 2 diabetes. However, little is known whether it influences insulin sensitivity directly or via its anti-inflammatory effect. The aim of this study was to assess the independent role of changes in inflammation status and weight loss on insulin sensitivity in this population.Overweight and obese nondiabetic participants without co-morbidities underwent a one-year weight loss intervention focused on caloric restriction and behavioral support. Markers of inflammation, body composition, anthropometric para-meters, and insulin sensitivity were recorded at baseline, 6, and 12 months. Insulin sensitivity was assessed with frequently sampled intravenous glucose tolerance test and Minimal Model. Twenty-eight participants (F: 15, M: 13, age 39±5 years, BMI 33.2±4.6 kg/m(2)) completed the study, achieving 9.4±6.9% weight loss, which was predominantly fat mass (7.7±5.6 kg, p<0.0001). Dietary intervention resulted in significant decrease in leptin, leptin-to-adiponectin ratio, hs-CRP, and IL-6 (all p<0.02), and improvement in HOMA-IR and Insulin Sensitivity Index (SI) (both p<0.001). In response to weight loss IL-1ß, IL-2, leptin, and resistin were significantly associated with insulin, sensitivity, whereas sICAM-1 had only marginal additive effect. Moderate weight loss in otherwise healthy overweight and obese individuals resulted in an improvement in insulin sensitivity and in the overall inflammation state; the latter played only a minimal independent role in modulating insulin sensitivity.

The Big Impact of Small Groups on College Drinking.

College drinking is a problem with severe academic, health, and safety consequences. The underlying social processes that lead to increased drinking activity are not well understood. Social Norms Theory is an approach to analysis and intervention based on the notion that students' misperceptions about the drinking culture on campus lead to increases in alcohol use. In this paper we develop an agent-based simulation model, implemented in MATLAB, to examine college drinking. Students' drinking behaviors are governed by their identity (and how others perceive it) as well as peer influences, as they interact in small groups over the course of a drinking event. Our simulation results provide some insight into the potential effectiveness of interventions such as social norms marketing campaigns.

Patterns of differential introgression in a salamander hybrid zone: inferences from genetic data and ecological niche modelling.

Hybrid zones have yielded considerable insight into many evolutionary processes, including speciation and the maintenance of species boundaries. Presented here are analyses from a hybrid zone that occurs among three salamanders -Plethodon jordani, Plethodon metcalfi and Plethodon teyahalee- from the southern Appalachian Mountains. Using a novel statistical approach for analysis of non-clinal, multispecies hybrid zones, we examined spatial patterns of variation at four markers: single-nucleotide polymorphisms (SNPs) located in the mtDNA ND2 gene and the nuclear DNA ILF3 gene, and the morphological markers of red cheek pigmentation and white flecks. Concordance of the ILF3 marker and both morphological markers across four transects is observed. In three of the four transects, however, the pattern of mtDNA is discordant from all other markers, with a higher representation of P. metcalfi mtDNA in the northern and lower elevation localities than is expected given the ILF3 marker and morphology. To explore whether climate plays a role in the position of the hybrid zone, we created ecological niche models for P. jordani and P. metcalfi. Modelling results suggest that hybrid zone position is not determined by steep gradients in climatic suitability for either species. Instead, the hybrid zone lies in a climatically homogenous region that is broadly suitable for both P. jordani and P. metcalfi. We discuss various selective (natural selection associated with climate) and behavioural processes (sex-biased dispersal, asymmetric reproductive isolation) that might explain the discordance in the extent to which mtDNA and nuclear DNA and colour-pattern traits have moved across this hybrid zone.

Analysis of genetic diversity in flowering dogwood natural stands using microsatellites: the effects of dogwood anthracnose.

Flowering dogwood (Cornus florida L.) populations recently have experienced severe declines caused by dogwood anthracnose. Mortality has ranged from 48 to 98%, raising the concern that genetic diversity has been reduced significantly. Microsatellite data were used to evaluate the level and distribution of genetic variation throughout much of the native range of the tree. Genetic variation in areas affected by anthracnose was as high as or higher than areas without die-offs. We found evidence of four widespread, spatially contiguous genetic clusters. However, there was little relationship between geographic distance and genetic difference. These observations suggest that high dispersal rates and large effective population sizes have so far prevented rapid loss of genetic diversity. The effects of anthracnose on demography and community structure are likely to be far more consequential than short-term genetic effects.

Pattern, process and geographic modes of speciation.

The tradition of classifying cases of speciation into discrete geographic categories (allopatric, parapatric and sympatric) fuelled decades of fruitful research and debate. Not surprisingly, as the science has become more sophisticated, this simplistic taxonomy has become increasingly obsolete. Geographic patterns are now reasonably well understood. Sister species are rarely sympatric, implying that sympatric speciation, it its most general sense, is rare. However, sympatric speciation, even in its most restricted population genetic sense, is possible. Several case studies have demonstrated that divergence has occurred in nature without geographic barriers to gene flow. Obviously, different sets of criteria for sympatric speciation will lead to different numbers of qualifying cases. But changing the rules of nomenclature to make 'sympatric speciation' more or less common does not constitute scientific progress. Advances in the study of speciation have come from studies of the processes that constrain or promote divergence, and how they are affected by geography.

Leadership in an academic discipline.

Leading an academic discipline poses moral and ethical challenges, requiring a special set of capabilities. Leadership in a clinical academic discipline involves leading the transformation of education, research, leadership and patient care. Daily struggles within strategic, political and cultural milieu are the norm and effective leaders are able to navigate through these struggles and see opportunities for growth.

Dobzhansky-Muller model of hybrid dysfunction supported by poor burst-speed performance in hybrid tiger salamanders.

Speciation may result from 'complementary' genetic differences that cause dysfunction when brought together in hybrids despite having no deleterious effects within pure species genomes. The theory of complementary genes, independently proposed by Dobzhansky and Muller, yields specific predictions about the genetics of hybrid fitness. Here, I show how alternative models of hybrid dysfunction can be compared using a simple multivariate analysis of hybrid indices calculated from molecular markers. I use the approach to fit models of hybrid dysfunction to swimming performance in hybrid tiger salamander larvae. Poor burst-speed performance is a dysfunction suggesting low vigour and could translate directly into low survival. My analyses show that the Dobzhansky-Muller model fits these data better than heterozygote disadvantage. The approach demonstrated here can be applied to a broad array of nonmodel species, potentially leading to important generalizations about the genetics of hybrid dysfunction.