Hybrid optimization method with general switching strategy for parameter estimation

This article is available from: http://www.biomedcentral.com/1752-0509/2/26[Background] Modeling and simulation of cellular signaling and metabolic pathways as networks of biochemical reactions yields sets of non-linear ordinary differential equations. These models usually depend on several parameters and initial conditions. If these parameters are unknown, results from simulation studies can be misleading. Such a scenario can be avoided by fitting the model to experimental data before analyzing the system. This involves parameter estimation which is usually performed by minimizing a cost function which quantifies the difference between model predictions and measurements. Mathematically, this is formulated as a non-linear optimization problem which often results to be multi-modal (non-convex), rendering local optimization methods detrimental.[Results] In this work we propose a new hybrid global method, based on the combination of an evolutionary search strategy with a local multiple-shooting approach, which offers a reliable and efficient alternative for the solution of large scale parameter estimation problems.[Conclusion] The presented new hybrid strategy offers two main advantages over previous approaches: First, it is equipped with a switching strategy which allows the systematic determination of the transition from the local to global search. This avoids computationally expensive tests in advance. Second, using multiple-shooting as the local search procedure reduces the multi-modality of the non-linear optimization problem significantly. Because multiple-shooting avoids possible spurious solutions in the vicinity of the global optimum it often outperforms the frequently used initial value approach (single-shooting). Thereby, the use of multiple-shooting yields an enhanced robustness of the hybrid approach.This work was supported by the European Community as part of the FP6 COSBICS Project (STREP FP6-512060), the German Federal Ministry of Education and Research, BMBF-project FRISYS (grant 0313921) and Xunta de Galicia (PGIDIT05PXIC40201PM).Peer reviewe

Choice of observational study design impacts on measurement of antipsychotic risks in the elderly: a systematic review

BACKGROUND: Antipsychotics are frequently and increasingly prescribed to treat the behavioural symptoms associated with dementia despite their modest efficacy. Evidence regarding the potential adverse events of antipsychotics is limited and little is known about the longer-term safety of these medicines in the elderly. The aim of this review was to determine the impact of the choice of observational study design and methods used to control for confounding on the measurement of antipsychotic risks in elderly patients. METHODS: We searched PUBMED and the Cochrane controlled trials register for double-blind randomised controlled trials (RCTs), meta-analyses and published observational studies of antipsychotics. RESULTS: Forty four studies were identified for the endpoints; death, cerebrovascular events, hip fracture and pneumonia. RCTs found a 20% to 30% increased risk of death, or an absolute increase of 1extra death per 100 patients with atypical antipsychotics compared to non-use. Cohort and instrumental variable analyses estimated between 2 to 7 extra deaths per 100 patients with conventional compared to atypical antipsychotics. RCTs found a 2 to 3 times increased risk of all cerebrovascular events with atypical antipsychotics compared to placebo and no association with serious stroke that required hospitalisation. Observational studies using cohort and self-controlled case-series designs reported similar results; no association where the endpoint was stroke causing hospitalisation and a doubling of risk when minor stroke was included. No RCTs were available for the outcome of hip fracture or pneumonia. Observational studies reported a 20% to 40% increased risk of hip fracture with both antipsychotic classes compared to non-use. The risk of pneumonia was a 2 to 3 times greater with both classes compared to non-use while a self-controlled case-series study estimated a 60% increased risk. Conventional antipsychotics were associated with a 50% greater hip fracture risk than atypical antipsychotics, while the risk of pneumonia was similar between the classes. CONCLUSIONS: Choice of observational study design is critical in studying the adverse effects of antispychotics. Cohort and instrumental variable analyses gave more consistent results to clinical studies for mortality outcomes as have self-controlled case-series for the risk of cerebrovascular events and stroke. Observational evidence has highlighted the potential for antipsychotics to be associated with serious adverse events that were not reported in RCTs including hip fracture and pneumonia. Good quality observational studies are required, that employ appropriate study designs that are robust towards unmeasured confounding, to confirm the potential excess risk of hip fracture and pneumonia with antipsychotics.Nicole Pratt, Elizabeth E. Roughead, Amy Salter and Philip Rya