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Missing heritability is a common problem in psychiatry that impedes precision medicine approaches to autism and other heritable complex disorders. This proof-of-concept study uses a systematic review and meta-analysis of the association between variants of the serotonin transporter promoter (5-HTTLPR) and autism to explore the hypothesis that some missing heritability can be explained using an optimum curve. A systematic literature search was performed to identify transmission disequilibrium tests on the short/long (S/L) 5-HTTLPR polymorphism in relation to autism. We analysed five American, seven European, four Asian and two American/European samples. We found no transmission preference in the joint samples and in Europe, preferential transmission of S in America and preferential transmission of L in Asia. Heritability will be underestimated or missed in genetic association studies if two alternative genetic variants are associated with the same disorder in different subsets of a sample. An optimum curve, relating a multifactorial biological variable that incorporates genes and environment to a score for a human trait, such as social competence, can explain this. We suggest that variants of functionally related genes will sometimes appear in fixed combinations at both sides of an optimum curve and propose that future association studies should account for such combinations.

Background, aim and scope In the context of environmental life cycle assessment (LCA), life cycle impact assessment (LCIA) is one of the central issues with respect to modelling and methodological data collection. The thesis described in this paper focusses on the assessment of toxicity-related impacts, and on the collection of normalisation data. A view on the complementary roles of LCA toxicity assessment on the one hand and human and environmental risk assessment (HERA) on the other is presented, and the global, spatially differentiated LCA toxicity assessment model GLOBOX for the assessment of organics and metals is described. Normalisation factors for the year 2000 are calculated on a global as well as on a European level. Goal Adding to the reliability and accuracy of LCIA takes a central place. A global coverage, spatial differentiation, and a distinction between potential and actual impacts are considered as important aspects in this context. Structure The thesis consists of seven chapters. The chapters 1 and 7 are a general introduction and discussion, respectively. The chapters 2 and 3 form a theoretical basis, focussing on the relationship between LCA toxicity assessment and HERA, and their respective roles in environmental protection. In chapters 4 and 5, the newly developed software model GLOBOX is described, along with conclusions, drawn from an analysis of the results of the model for the substance nitrobenzene. Chapter 6 describes a practical update of LCA normalisation for all LCA impact categories. Conclusion LCA toxicity assessment and HERA are distinct tools with different goals and outputs, but with an overlap with respect to environmental fate and human intake calculation. Although they cannot be merged, it is proposed to combine them in a common software model, which would offer harmonised results with respect to both types of outputs. Existing multimedia fate and exposure models form a useful basis, but to be applicable in LCA, they should combine global coverage with spatial differentiation, and they should allow for the assessment of metal emissions. The GLOBOX model offers this combination of features. At the level of separate countries and seas, spatial differentiation of environmental and human exposure characteristics turns out to show large differences between regions with respect to the toxic impacts, calculated to result from a certain emission of the test substance nitrobenzene. Finally, the GLOBOX model demonstrates that it is possible not only in HERA, but also in LCIA, to assess actual environmental impacts, along with the potential impacts on which LCA traditionally focuses.

Linkages between Human and Environmental Risk Assessment (HERA) and Life-Cycle Assessment (LCA) can be analyzed at three levels: the basic equations to describe environmental behavior and dose-response relationships of chemicals; the overall model structure of these tools; and the applications of the tools. At level 1 few differences exist: both tools use essentially the same fate and effect models, including their coefficients and data. At level 2 distinctive differences emerge: regional or life-cycle perspective, emission pulses or fluxes, scope of chemicals and types of impacts, use of characterization factors, spatial and temporal detail, aggregation of effects, and the functional unit as basis of the assessment. Although the two tools typically differ in all these aspects, only the functional unit issue renders the tools fundamentally different, expressing itself also in some main characteristics of the modeling structure. This impedes full integration, which is underpinned in mathematical terms. At level 3 the aims of the tools are complementary: quantified risk estimates of chemicals for HERA versus quantified product assessment for LCA. Here, beneficial synergism is possible between the two tools, as illustrated by some cases. These also illustrate that where full integration is suggested, in practice this is not achieved, thus in fact supporting the conclusions.

Methods for life cycle assessment of products (LCA) are most often based on the general prevention principle, as opposed to the risk minimization principle. Here, the desirability and feasibility of a combined approach are discussed, along with the conditions for elaboration in the framework of LCA methodology, and the consequences for LCA practice. A combined approach provides a separate assessment of above and below threshold pollution, offering the possibility to combat above threshold impacts with priority. Spatial differentiation in fate, exposure, and effect modelling is identified to play a central role in the implementation. The collection of region-specific data turns out to be the most elaborate requirement for the implementation in both methodology and practice. A methodological framework for the construction of characterization factors is provided. Along with spatial differentiation of existing parameters, two newly introduced spatial parameters play a key role: the sensitivity factor and the threshold factor. The practicability of the proposed procedure is illustrated by an example of its application. Providing a reasonable data availability, the development of separate LCA characterization factors for the respective assessment of pollution levels above and below environmental threshold values seems to be a feasible task that may add to LCA credibility.

-DOI: http://dx.doi.org/10.1065/lca2006.04.008Goal, Scope and Background CML has contributed to the development of life cycle decision support tools, particularly Substance / Material Flow Analysis (SFA respectively MFA) and Life Cycle Assessment (LCA). Ever since these tools emerged there have been discussions on how these tools relate to each other, and how they relate to more traditional tools. Remarkably little, however, has been published on these relationships from an empirical side: which combinations of tools have actually been used, and what is the added value of combining tools in practical case studies. In this paper, we report on CML's experience in this field by presenting a number of case studies with their related research questions, for which different tools were deployed. Methods Three case studies are discussed: 1) Waste water treatment: various options for waste water treatment have been assessed on their eco-efficiency, using SFA to comment on the influence of these options on the flows of certain substances in the water system of a geographical area and a combination of LCA and life cycle costing (LCC) to assess the life-cycle impacts and costs of these options; 2) Prioritization of environmental policy measures: A methodology has been developed to prioritize environmental policy measures and investments within companies based on both the environmental impacts and the costs of these measures; and 3) Environmental weighting of materials: to add an environmental dimension to standard MFA accounts, materials were weighted with cradle-to-grave impact factors based on LCA data and impact assessment factors. Results and Discussion For each of these cases, the research questions at stake, the tools applied, the results and the added value, limitations and problems of combining the tools are reported. Conclusionsand Perspective. Based on these experiences, it is concluded that using several tools to address a complicated problem is not only a theoretical proposal, but also something that has been applied successfully in a variety of practical situations. Furthermore, using several tools in combination does not necessarily lead to an increased information supply to decisionmakers. Instead, it may contribute to the comprehensibility and ease of interpretation of the information that would have been provided by using a single tool. Finally, it is concluded that there is not one generally valid protocol for which tools to use for which question. The essential idea of using a combination of tools is exactly the fact that research questions are not simple by nature and cannot be generalized into protocols.

For the purpose of chemical risk management and decision-making, chemical risk assessment (RA) and life-cycle assessment (LCA) of products are indispensable tools. In this paper the authors provide an overview of their respective modes of application, based on the goals for which they have been designed, and the underlying modelling structures. LCA is shown to differ in a fundamental way from RA, offering distinctive possibilities for serving management and policy goals. The functional unit plays a key role, both in the capacities of LCA and in how LCA differs from RA. Despite these differences, the authors conclude the paper with a proposal for the integration of RA and LCA into a common tool that combines them without the loss of their individual advantages. Reprinted by permission of Greenleaf Publishing