Bayes optimal informer sets for early-stage drug discovery

An important experimental design problem in early-stage drug discovery is how to prioritize available compounds for testing when very little is known about the target protein. Informer-based ranking (IBR) methods address the prioritization problem when the compounds have provided bioactivity data on other potentially relevant targets. An IBR method selects an informer set of compounds, and then prioritizes the remaining compounds on the basis of new bioactivity experiments performed with the informer set on the target. We formalize the problem as a two-stage decision problem and introduce the Bayes Optimal Informer SEt (BOISE) method for its solution. BOISE leverages a flexible model of the initial bioactivity data, a relevant loss function, and effective computational schemes to resolve the two-step design problem. We evaluate BOISE and compare it to other IBR strategies in two retrospective studies, one on protein-kinase inhibition and the other on anticancer drug sensitivity. In both empirical settings BOISE exhibits better predictive performance than available methods. It also behaves well with missing data, where methods that use matrix completion show worse predictive performance.     

Savior Siblings,Parenting and the Moral Valorization of Children

Philosophy has long been concerned with ‘moral status’. Discussions about the moral status of children, however, seem often to promote confusion rather than clarity. Using the creation of ‘savior siblings’ as an example, this paper provides a philosophical critique of the moral status of children and the moral relevance of parenting and the role that formative experience, regret and relational autonomy play in parental decisions. We suggest that parents make moral decisions that are guided by the moral significance they attach to children, to sick children and most importantly, to a specific sick child (theirs). This moral valorization is rarely made explicit and has generally been ignored by both philosophers and clinicians in previous critiques. Recognizing this, however, may transform not only the focus of bioethical discourse but also the policies and practices surrounding the care of children requiring bone marrow or cord blood transplantation by better understanding the values at stake behind parental decision making.     

Developing Autonomy and Transitional Paternalism

Adolescents, in many jurisdictions, have the power to consent to life saving treatment but not necessarily the power to refuse it. A recent defence of this asymmetry is Neil Manson's theory of ‘transitional paternalism’. Transitional paternalism holds that such asymmetries are by‐products of sharing normative powers. However, sharing normative powers by itself does not entail an asymmetry because transitional paternalism can be implemented in two ways. Manson defends the asymmetry‐generating version of transitional paternalism in the clinical context, arguing that it maximizes respect for adolescent autonomy. This article offers an alternative argument in favour of the asymmetry‐generating form of transitional paternalism, one that makes appeal to obligations that individuals have to develop self‐governance in others. We should share normative powers asymmetrically in the clinical context for three reasons. First, the asymmetric version of transitional paternalism takes seriously duties to support adolescents’ developing autonomy, alongside other duties that adults have to young people. It does so by enabling young people to be involved in important decisions that they would otherwise be excluded from. This is of value because participation of this sort is central to the cultivation of their self‐governance. Second, only the asymmetric version gives young people a voice in respect of all clinical actions, and only the asymmetric version leaves open the possibility that the coarse lines of legislation might be ‘fine‐tuned’ in individual cases. Third, the asymmetric sharing of normative powers is consistent with the kind of social arrangements that best support autonomy.     

The combined effects of the 5‐ HTTLPR and HTR1A rs6295 polymorphisms modulate decision making in schizophrenia patients

Decision making ability has been reported to be impaired in schizophrenia patients, but no research has examined the genetic bases of this impairment. This study investigated how decision making was affected by the genetic variants in the serotonin transporter gene (triallelic 5‐ HTTLPR) and serotonin receptor 1A gene (rs6295) and their interaction in 465 schizophrenia patients and 448 healthy controls. The Iowa Gambling Task (IGT) was used to evaluate decision making under ambiguity (the first 40 trials) and decision making under risk (the last 60 trials). Results showed that, among the patients, the main effects of 5‐ HTTLPR (F_2,16 = 6.54, P = 0.002) and HTR1A rs6295 (F_2,16 = 3.87, P = 0.021) polymorphisms and their interaction effect (F_4,16 = 3.32, P = 0.005) were significant for the first 40 trials, with the GG genotype of HTR1A rs6295, the L′L′ genotype of 5‐ HTTLPR and the GG‐L′L′ combination showing poorer IGT performance than their counterparts. Results for the healthy controls showed a similar pattern but did not reach statistical significance. No significant effects were found for the last 60 trials. These results are discussed in terms of their implications for our understanding of the genetic mechanisms of decision making in schizophrenia patients as well as healthy adults.     

Who should Decide for the Unrepresented?

Unrepresented patients lack the capacity to make medical decisions for themselves, have no clear documentation of preferences for medical treatment, and have no surrogate decision maker or obvious candidate for that role. There is no consensus about who should serve as the decision maker for these patients, particularly regarding whether to continue or to limit life‐sustaining treatment. Several authors have argued that ethics committees should play this role rather than the patient's treating physician, a common current default. We argue that concerns about the adequacy of physicians as surrogates are either empirically unfounded or apply equally to ethics committees. We suggest that physicians should be the primary decision maker for the unrepresented because of their fiduciary duties toward their patients. As part of the process of fulfilling these duties, they should seek the advice of third parties such as ethic committees; but final end‐of‐life decision‐making for the unrepresented should rest with the treating physician.     

Well Differentiated Follicular Neoplasms of the Thyroid: Reproducibility and Validity of A''Decision Tree''Classification Based On Nucleolar and Karyometric Features

This study was conducted on fine-needle aspirates of well differentiated follicular neoplasms of the thyroid. A 'decision tree' classification based on the percentage of nucleolated nuclei, percentage of nuclei with two or more nucleoli and mean major nuclear diameter was adopted. We observed that the reproducibility and the validity of the follicular adenoma vs follicular carcinoma discrimination are greater than in the subjective evaluation. Moreover, similar classification results were obtained when measurements were performed either with a fully automated image analysis system or with semiautomatic or manual instrumentation. As for reproducibility of the inter-instrument comparisons, the k statistic values ranged from 0.85 to 1.00 (mean value 0.90, that is, an 'almost perfect' degree of agreement); in the subjective evaluations, the inter-observer comparisons showed values ranging from 0.20 to 0.56 (mean value 0.37, that is, 'fair'). In the decision tree classification, feature value thresholds were selected in order to have specificity of 100% and the predictive value of a positive result (carcinoma) of 100%; accuracy was 87% (range 86-89%), sensitivity 74% (71-79%), the predictive value of a negative result (adenoma) 79% (78-82%). In the subjective evaluation the values were as follows: accuracy 67% (64-71%), sensitivity 57% (50-64%), specificity 77% (71-79%), predictive value of a negative result (adenoma) 64% (61-69%), predictive value of a positive result (carcinoma) 71% (67-75%). The conclusion is that, by using a routine microscope equipped with a micrometer, the preoperative diagnosis of follicular carcinoma from smears can be formulated with a high degree of certainty.     

In the Same Boat? A Comparative Analysis of the Approaches of Russia and Canada in the Negotiation of the IMO’s Mandatory Polar Code

Abstract

In the field of Arctic shipping, Canada and the Russian Federation have enacted extensive unilateral national regulations cognizant of Article 234, UN Convention on the Law of the Sea. On the global level, both states have been important actors in negotiating the International Maritime Organization’s mandatory Polar Code, a legal instrument with implications for regulations at the national level. This article compares and contrasts the approaches, positions, and arguments of Canada and Russia especially regarding national systems to control navigation and vessel-source pollution. The results suggest different emphases stemming from the two states’ political and economic realities and capacities.     

Pig cognitive bias affects the conversion of muscle into meat by antioxidant and autophagy mechanisms

Slaughter is a crucial step in the meat production chain that could induce psychological stress on each animal, resulting in a physiological response that can differ among individuals. The aim of this study was to investigate the relationship between an animal’s emotional state, the subsequent psychological stress at slaughter and the cellular damage as an effect. In all, 36 entire male pigs were reared at an experimental farm and a cognitive bias test was used to classify them into positive bias (PB) or negative bias (NB) groups depending on their decision-making capabilities. Half of the animals, slaughtered in the same batch, were used for a complete study of biomarkers of stress, including brain neurotransmitters and some muscle biomarkers of oxidative stress. After slaughter, specific brain areas were excised and the levels of catecholamines (noradrenaline (NA) and dopamine (DA)) and indoleamines (5-hydroxyindoleacetic acid and serotonin (5HT)) were analyzed. In addition, muscle proteasome activity (20S), antioxidant defence (total antioxidant activity (TAA)), oxidative damage (lipid peroxidation (LPO)) and autophagy biomarkers (Beclin-1, microtubule-associated protein I light chain 3 (LC3-I) and LC3-II) were monitored during early postmortem maturation (0 to 24 h). Compared with PB animals, NB pigs were more susceptible to stress, showing higher 5HT levels (P<0.01) in the hippocampus and lower DA (P<0.001) in the pre-frontal cortex. Furthermore, NB pigs had more intense proteolytic processes and triggered primary muscle cell survival mechanisms immediately after slaughter (0 h postmortem), thus showing higher TAA (P<0.001) and earlier proteasome activity (P<0.001) and autophagy (Beclin-1, P<0.05; LC3-II/LC3-I, P<0.001) than PB pigs, in order to counteract the induced increase in oxidative stress, that was significantly higher in the muscle of NB pigs at 0 h postmortem (LPO, P<0.001). Our study is the first to demonstrate that pig’s cognitive bias influences the animal’s susceptibility to stress and has important effects on the postmortem muscle metabolism, particularly on the cell antioxidant defences and the autophagy onset. These results expand the current knowledge regarding biomarkers of animal welfare and highlight the potential use of biomarkers of the proteasome, the autophagy (Beclin-1, LC3-II/LC3-I ratio) and the muscle antioxidant defence (TAA, LPO) for detection of peri-slaughter stress.     

Decision Tree-PLS (DT-PLS) algorithm for the development of process: Specific local prediction models

This work presents a novel multivariate statistical algorithm, Decision Tree-PLS (DT-PLS), to improve the prediction and understanding of dynamic processes based on local partial least square regression (PLSR) models for characteristic process groups defined based on Decision Tree (DT) analysis. The DT-PLS algorithm is successfully applied to two different cell culture data sets, one obtained from bioreactors of 3.5 L lab scale and the other obtained from the 15 ml ambr microbioreactor system. Substantial improvement in the predictive capabilities of the model can be achieved based on the localization compared to the classical PLSR approach, which is implemented in the commercially available packages. Additionally, the differences in the model parameters of the local models suggest that the governing process variables vary for the different process regimes indicating the different states of the cell under different process conditions.