MID3: Mission Impossible or Model-Informed Drug Discovery and Development? Point-Counterpoint Discussions on Key Challenges

MID3: Mission Impossible, or Model‐Informed, Drug Discovery and Development? At the 2019 American Society for Clinical Pharmacology and Therapeutics (ASCPT) annual meeting, point‐counterpoint discussions were held on key challenges that limit, and future directions that enhance the adoption of model‐informed drug discovery and development (MID3) across the drug discovery, development, regulatory, and utilization continuum. We envision that the opportunities discussed and lessons learned from having contrasting perspectives on issues that lack consensus may aid our discipline in more effectively implementing MID3 principles

Target Cueing Provides Support for Target- and Resource-Based Models of the Attentional Blink

The attentional blink (AB) describes a time-based deficit in processing the second of two masked targets. The AB is attenuated if successive targets appear between the first and final target, or if a cueing target is positioned before the final target. Using various speeds of stimulus presentation, the current study employed successive targets and cueing targets to confirm and extend an understanding of target-target cueing in the AB. In Experiment 1, three targets were presented sequentially at rates of 30 msec/item or 90 msec/item. Successive targets presented at 90 msec improved performance compared with non-successive targets. However, accuracy was equivalently high for successive and non-successive targets presented at 30 msec/item, suggesting that–regardless of whether they occurred consecutively–those items fell within the temporally defined attentional window initiated by the first target. Using four different presentation speeds, Experiment 2 confirmed the time-based definition of the AB and the success of target-cueing at 30 msec/item. This experiment additionally revealed that cueing was most effective when resources were not devoted to the cue, thereby implicating capacity limitations in the AB. Across both experiments, a novel order-error measure suggested that errors tend to decrease with an increasing duration between the targets, but also revealed that certain stimulus conditions result in stable order accuracy. Overall, the results are best encapsulated by target-based and resource-sharing theories of the AB, which collectively value the contributions of capacity limitations and optimizing transient attention in time

The impact of predation by marine mammals on Patagonian toothfish longline fisheries

Predatory interaction of marine mammals with longline fisheries is observed globally, leading to partial or complete loss of the catch and in some parts of the world to considerable financial loss. Depredation can also create additional unrecorded fishing mortality of a stock and has the potential to introduce bias to stock assessments. Here we aim to characterise depredation in the Patagonian toothfish (Dissostichus eleginoides) fishery around South Georgia focusing on the spatio-temporal component of these interactions. Antarctic fur seals (Arctocephalus gazella), sperm whales (Physeter macrocephalus), and orcas (Orcinus orca) frequently feed on fish hooked on longlines around South Georgia. A third of longlines encounter sperm whales, but loss of catch due to sperm whales is insignificant when compared to that due to orcas, which interact with only 5% of longlines but can take more than half of the catch in some cases. Orca depredation around South Georgia is spatially limited and focused in areas of putative migration routes, and the impact is compounded as a result of the fishery also concentrating in those areas at those times. Understanding the seasonal behaviour of orcas and the spatial and temporal distribution of “depredation hot spots” can reduce marine mammal interactions, will improve assessment and management of the stock and contribute to increased operational efficiency of the fishery. Such information is valuable in the effort to resolve the human-mammal conflict for resources

Integrating evolution into ecological modelling: accommodating phenotypic changes in agent based models.

PMCID: PMC3733718This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Evolutionary change is a characteristic of living organisms and forms one of the ways in which species adapt to changed conditions. However, most ecological models do not incorporate this ubiquitous phenomenon. We have developed a model that takes a 'phenotypic gambit' approach and focuses on changes in the frequency of phenotypes (which differ in timing of breeding and fecundity) within a population, using, as an example, seasonal breeding. Fitness per phenotype calculated as the individual's contribution to population growth on an annual basis coincide with the population dynamics per phenotype. Simplified model variants were explored to examine whether the complexity included in the model is justified. Outputs from the spatially implicit model underestimated the number of individuals across all phenotypes. When no phenotype transitions are included (i.e. offspring always inherit their parent's phenotype) numbers of all individuals are always underestimated. We conclude that by using a phenotypic gambit approach evolutionary dynamics can be incorporated into individual based models, and that all that is required is an understanding of the probability of offspring inheriting the parental phenotype

Latent cluster analysis of ALS phenotypes identifies prognostically differing groups

BACKGROUND Amyotrophic lateral sclerosis (ALS) is a degenerative disease predominantly affecting motor neurons and manifesting as several different phenotypes. Whether these phenotypes correspond to different underlying disease processes is unknown. We used latent cluster analysis to identify groupings of clinical variables in an objective and unbiased way to improve phenotyping for clinical and research purposes. METHODS Latent class cluster analysis was applied to a large database consisting of 1467 records of people with ALS, using discrete variables which can be readily determined at the first clinic appointment. The model was tested for clinical relevance by survival analysis of the phenotypic groupings using the Kaplan-Meier method. RESULTS The best model generated five distinct phenotypic classes that strongly predicted survival (p<0.0001). Eight variables were used for the latent class analysis, but a good estimate of the classification could be obtained using just two variables: site of first symptoms (bulbar or limb) and time from symptom onset to diagnosis (p<0.00001). CONCLUSION The five phenotypic classes identified using latent cluster analysis can predict prognosis. They could be used to stratify patients recruited into clinical trials and generating more homogeneous disease groups for genetic, proteomic and risk factor research

Towards Erlang Verification by Term Rewriting

The final publication is available at Springer via http://dx.doi.org/10.1007/978-3-319-14125-1_7This paper presents a transformational approach to the verification of Erlang programs. We define a stepwise transformation from (first-order) Erlang programs to (non-deterministic) term rewrite systems that compute an overapproximation of the original Erlang program. In this way, existing techniques for term rewriting become available. Furthermore, one can use narrowing as a symbolic execution extension of rewriting in order to design a verification technique. We illustrate our approach with some examples, including a deadlock analysis of a simple Erlang program.Vidal Oriola, GF. (2013). Towards Erlang Verification by Term Rewriting. En Logic-Based Program Synthesis and Transformation. Springer. 109-126. doi:10.1007/978-3-319-14125-1_7S109126Albert, E., Arenas, P., Gómez-Zamalloa, M.: Symbolic Execution of Concurrent Objects in CLP. In: Russo, C., Zhou, N.-F. (eds.) PADL 2012. LNCS, vol. 7149, pp. 123–137. Springer, Heidelberg (2012)Albert, E., Vidal, G.: The narrowing-driven approach to functional logic program specialization. New Generation Computing 20(1), 3–26 (2002)Joe, A., Robert, V., Williams, M.: Concurrent programming in ERLANG. Prentice Hall (1993)Arts, T., Earle, C.B., Derrick, J.: Development of a verified Erlang program for resource locking. STTT 5(2–3), 205–220 (2004)Baader, F., Nipkow, T.: Term Rewriting and All That. Cambridge University Press (1998)Caballero, R., Martin-Martin, E., Riesco, A., Tamarit, S.: A Declarative Debugger for Sequential Erlang Programs. In: Veanes, M., Viganò, L. (eds.) TAP 2013. LNCS, vol. 7942, pp. 96–114. Springer, Heidelberg (2013)Claessen, K., Svensson, H.: A semantics for distributed Erlang. In: Sagonas, K.F., Armstrong, J. (eds.). In: Proc. of the 2005 ACM SIGPLAN Workshop on Erlang, pp. 78–87. ACM (2005)Earle, C.B.: Symbolic program execution using the Erlang verification tool. In: Alpuente, M. (eds.) 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Estimating maize genetic erosion in modernized smallholder agriculture

Replacement of crop landraces by modern varieties is thought to cause diversity loss. We studied genetic erosion in maize within a model system; modernized smallholder agriculture in southern Mexico. The local seed supply was described through interviews and in situ seed collection. In spite of the dominance of commercial seed, the informal seed system was found to persist. True landraces were rare and most informal seed was derived from modern varieties (creolized). Seed lots were characterized for agronomical traits and molecular markers. We avoided the problem of non-consistent nomenclature by taking individual seed lots as the basis for diversity inference. We defined diversity as the weighted average distance between seed lots. Diversity was calculated for subsets of the seed supply to assess the impact of replacing traditional landraces with any of these subsets. Results were different for molecular markers, ear- and vegetative/flowering traits. Nonetheless, creolized varieties showed low diversity for all traits. These varieties were distinct from traditional landraces and little differentiated from their ancestral stocks. Although adoption of creolized maize into the informal seed system has lowered diversity as compared to traditional landraces, genetic erosion was moderated by the distinct features offered by modern varieties

A method for estimation of elasticities in metabolic networks using steady state and dynamic metabolomics data and linlog kinetics

BACKGROUND: Dynamic modeling of metabolic reaction networks under in vivo conditions is a crucial step in order to obtain a better understanding of the (dis)functioning of living cells. So far dynamic metabolic models generally have been based on mechanistic rate equations which often contain so many parameters that their identifiability from experimental data forms a serious problem. Recently, approximative rate equations, based on the linear logarithmic (linlog) format have been proposed as a suitable alternative with fewer parameters. RESULTS: In this paper we present a method for estimation of the kinetic model parameters, which are equal to the elasticities defined in Metabolic Control Analysis, from metabolite data obtained from dynamic as well as steady state perturbations, using the linlog kinetic format. Additionally, we address the question of parameter identifiability from dynamic perturbation data in the presence of noise. The method is illustrated using metabolite data generated with a dynamic model of the glycolytic pathway of Saccharomyces cerevisiae based on mechanistic rate equations. Elasticities are estimated from the generated data, which define the complete linlog kinetic model of the glycolysis. The effect of data noise on the accuracy of the estimated elasticities is presented. Finally, identifiable subset of parameters is determined using information on the standard deviations of the estimated elasticities through Monte Carlo (MC) simulations. CONCLUSION: The parameter estimation within the linlog kinetic framework as presented here allows the determination of the elasticities directly from experimental data from typical dynamic and/or steady state experiments. These elasticities allow the reconstruction of the full kinetic model of Saccharomyces cerevisiae, and the determination of the control coefficients. MC simulations revealed that certain elasticities are potentially unidentifiable from dynamic data only. Addition of steady state perturbation of enzyme activities solved this problem

Successful new product development by optimizing development process effectiveness in highly regulated sectors: the case of the Spanish medical devices sector

Rapid development and commercialization of new products is of vital importance for small and medium sized enterprises (SME) in regulated sectors. Due to strict regulations, competitive advantage can hardly be achieved through the effectiveness of product concepts only. If an SME in a highly regulated sector wants to excell in new product development (NPD) performance, the company should focus on the flexibility, speed, and productivity of its NPD function: i.e. the development process effectiveness. Our main research goals are first to explore if SMEs should focus on their their development process effectiveness rather than on their product concept effectiveness to achieve high NPD performance; and second, to explore whether a shared pattern in the organization of the NPD function can be recognized to affect NPD performance positively. The medical devices sector in Spain is used as an example of a\ud highly regulated sector. A structured survey among 11 SMEs, of which 2 were studied also as in in-depth case studies, led to the following results. First of all, indeed the companies in the dataset which focused on the effectiveness of their development process, stood out in NPD performance. Further, the higher performing companies did have a number of commonalities in the organisation of their NPD function: 1) The majority of the higher performing firms had an NPD strategy characterized by a predominantly incremental project portfolio.\ud 2) a) Successful firms with an incremental project portfolio combined this with a functional team structure b) Successful firms with a radical project portfolio combined this with a heavyweight or autonomous team structure.\ud 3) A negative reciprocal relationship exists between formalization of the NPD processes and the climate of the NPD function, in that a formalized NPD process and an innovative climate do not seem to reinforce each other. Innovative climate combined with an informal NPD process does however contribute positively to NPD performance. This effect was stronger in combination with a radical project portfolio. The highest NPD performance was measured for companies focusing mainly on incremental innovation. It is argued that in highly regulated sectors, companies with an incremental product portfolio would benefit from employing a functional structure. Those companies who choose for a more radical project portfolio in highly regulated sectors should be aware\ud that they are likely to excell only in the longer term by focusing on strategic flexibility. In their NPD organization, they might be well advised to combine informal innovation processes with an innovative climate