Formulating genome-scale kinetic models in the post-genome era

The biological community is now awash in high-throughput data sets and is grappling with the challenge of integrating disparate data sets. Such integration has taken the form of statistical analysis of large data sets, or through the bottom–up reconstruction of reaction networks. While progress has been made with statistical and structural methods, large-scale systems have remained refractory to dynamic model building by traditional approaches. The availability of annotated genomes enabled the reconstruction of genome-scale networks, and now the availability of high-throughput metabolomic and fluxomic data along with thermodynamic information opens the possibility to build genome-scale kinetic models. We describe here a framework for building and analyzing such models. The mathematical analysis challenges are reflected in four foundational properties, (i) the decomposition of the Jacobian matrix into chemical, kinetic and thermodynamic information, (ii) the structural similarity between the stoichiometric matrix and the transpose of the gradient matrix, (iii) the duality transformations enabling either fluxes or concentrations to serve as the independent variables and (iv) the timescale hierarchy in biological networks. Recognition and appreciation of these properties highlight notable and challenging new in silico analysis issues

Developing an intervention to facilitate family communication about inherited genetic conditions, and training genetic counsellors in its delivery.

Many families experience difficulty in talking about an inherited genetic condition that affects one or more of them. There have now been a number of studies identifying the issues in detail, however few have developed interventions to assist families. The SPRinG collaborative have used the UK Medical Research Council's guidance on Developing and Evaluating Complex Interventions, to work with families and genetic counsellors (GCs) to co-design a psycho-educational intervention to facilitate family communication and promote better coping and adaptation to living with an inherited genetic condition for parents and their children (<18 years). The intervention is modelled on multi-family discussion groups (MFDGs) used in psychiatric settings. The MFDG was developed and tested over three phases. First focus groups with parents, young people, children and health professionals discussed whether MFDG was acceptable and proposed a suitable design. Using evidence and focus group data, the intervention and a training manual were developed and three GCs were trained in its delivery. Finally, a prototype MFDG was led by a family therapist and co-facilitated by the three GCs. Data analysis showed that families attending the focus groups and intervention thought MFDG highly beneficial, and the pilot sessions had a significant impact on their family' functioning. We also demonstrated that it is possible to train GCs to deliver the MFDG intervention. Further studies are now required to test the feasibility of undertaking a definitive randomised controlled trial to evaluate its effectiveness in improving family outcomes before implementing into genetic counselling practice.The National Institute of Health Research funded the study but any views expressed do not necessarily reflect those of the Authority. Funded by NIHR reference number: RP-DG-1211-10015

Parents' Experiences of Receiving the Initial Positive Newborn Screening (NBS) Result for Cystic Fibrosis and Sickle Cell Disease

The clinical advantages of the newborn screening programme (NBS) in the UK are well described in the literature. However, there has been little exploration of the psychosocial impact on the family. This study followed the principles of grounded theory to explore parents' experiences of receiving the initial positive NBS result for their child with cystic fibrosis (CF) or sickle cell disease (SCD). Semi-structured, qualitative interviews were conducted with 22 parents (12 mothers and 10 fathers) whose children had been diagnosed with CF or SCD via NBS and were under the age of 1 year at the time of interview. The main themes that arose from the data were; parents previous knowledge of the condition and the NBS programme, the method of delivery and parental reactions to the result, sharing the results with others, the impact on parental relationships and support strategies. Study conclusions indicate that most parents thought initial positive NBS results should be delivered by a health professional with condition specific knowledge, preferably with both parents present. Genetic counselling needs to include a focus on the impact of NBS results on parental relationships. Careful consideration needs to be given to strategies to support parents of babies who have positive NBS results both in terms of the psychological health and to assist them in sharing the diagnosis

Climate change mitigation with technology spillovers

We explore the implications of an increase in clean technology spillovers between developed and developing countries. We build a game of abatements in which players are linked with technology spillovers determined by an initial choice of absorptive capacities by developing countries. We show that, within a non-cooperative framework, the response of clean technology investments in developed countries to an increase in cross-country technology spillovers is ambiguous. If the marginal benefits of these additional abatements are not sufficiently high, developed countries have a strategic incentive to decrease investments. Such a strategic response jeopardizes the initial effects of an increase in technology spillovers on climate change mitigation and decreases the incentives for developing countries to enhance their absorptive capacities

Endogenous Risks and Learning in Climate Change Decision Analysis

We analyze the effects of risks and learning on climate change decisions. A two-stage, dynamic, climate change stabilization problem is formulated. The explicit incorporation of ex-post learning induces risk aversion among ex-ante decisions, which is characterized in linear models by VaR- and CVaR-type risk measures. Combined with explicit introduction of "safety" constraints, it creates a "hit-or-miss" type decision-making situation and shows that, even in linear models, learning may lead to either less-or more restrictive ex-ante emission reductions. We analyze stylized elements of the model in order to identify the key factors driving outcomes, in particular, the critical role of quantiles of probability distributions characterizing key uncertainties

Environmental regulation induced foreign direct investment

The last decade has witnessed a renewed interest in the relationship between environmental regulations and international capital flows. However, empirical studies have so far failed to find conclusive evidence for this so-called pollution haven or race to the bottom effect where foreign direct investment (FDI) is assumed to be attracted to low regulation countries, regions or states. In this paper we present a simple theoretical framework to demonstrate that greater stringency in environmental standards can lead to a strategic increase in capital inflows which we refer to as environmental regulation induced FDI. Our result reveals a possible explanation for the mixed results in the empirical literature and provides an illustration of the conditions under which environmental regulations in the host country can affect the location decision of foreign firms

Optimal redistributive tax and education policies in general equilibrium

This paper studies optimal linear and non-linear income taxes and education subsidies in two-type models with endogenous human capital formation, endogenous labor supply, and endogenous wage rates. Assuming constant human capital elasticities, human capital investment should be efficient under optimal linear policies, whether general equilibrium effects are present or not. Hence, education subsidies should not be used for distributional reasons. Due to general equilibrium effects, optimal linear income taxes may even become negative. Optimal non-linear policies exploit general equilibrium effects for redistribution. The high-skilled type optimally has a negative marginal income tax rate and a positive marginal education subsidy. The low-skilled type optimally faces a positive marginal income tax rate and a marginal tax on education. Simulations demonstrate that general equilibrium effects have only a modest effect on optimal non-linear policies

The role of knowledge, primary care and community engagement to improve breast-screening access for Pakistani women in the United Kingdom: a secondary analysis of a qualitative study

Objective: Breast cancer incidence is rising among Pakistani women in the United Kingdom. However, uptake of breast screening remains low. This study aimed to improve access to breast screening for British-Pakistani women by exploring their knowledge of breast cancer and the role of primary care and community networks to support screening access amongst British-Pakistani women. Methods: We undertook a secondary qualitative analysis of 18 semi-structured interviews with British-Pakistani women from East Lancashire in the United Kingdom. Anonymized transcripts of the interviews were used for a thematic analysis. Results: Three themes were identified in the interviewees’ responses: (i) ‘Women’s knowledge of breasts and breast cancer’, which described how a cultural taboo exists around Pakistani women’s bodies and around breast cancer; (ii) ‘Role of primary care’, which detailed how General Practitioners can support informed decisions and offer a trusted and valued information source; (iii) ‘Community engagement’, which described the potential to disseminate breast-screening information through the whole community, including primary care providers, all family members and mosques. Conclusions: Our analysis suggested three main targets for future interventions to improve access to breast screening for British-Pakistani women: (i) co-produced strategies to increase knowledge of breasts and breast screening; (ii) greater collaboration with local General Practitioners to support women to make informed choices about screening; and (iii) community engagement involving General Practitioners and community leaders, to inform everyone – not just screening-age women – about breast cancer and screening

Training Genetic Counsellors to Deliver an Innovative Therapeutic Intervention: their views and experience of facilitating multi-family discussion groups

Innovations in clinical genetics have increased diagnosis, treatment and prognosis of inherited genetic conditions (IGCs). This has led to an increased number of families seeking genetic testing and / or genetic counselling and increased the clinical load for genetic counsellors (GCs). Keeping pace with biomedical discoveries, interventions are required to support families to understand, communicate and cope with their Inherited Genetic Condition. The Socio-Psychological Research in Genomics (SPRinG) collaborative have developed a new intervention, based on multi-family discussion groups (MFDGs), to support families affected by IGCs and train GCs in its delivery. A potential challenge to implementing the intervention was whether GCs were willing and able to undergo the training to deliver the MFDG. In analysing three multi-perspective interviews with GCs, this paper evaluates the training received. Findings suggests that MFDGs are a potential valuable resource in supporting families to communicate genetic risk information and can enhance family function and emotional well-being. Furthermore, we demonstrate that it is feasible to train GCs in the delivery of the intervention and that it has the potential to be integrated into clinical practice. Its longer term implementation into routine clinical practice however relies on changes in both organisation of clinical genetics services and genetic counsellors' professional development