Sampling methods for exploring between-subject variability in cardiac electrophysiology experiments.

Between-subject and within-subject variability is ubiquitous in biology and physiology, and understanding and dealing with this is one of the biggest challenges in medicine. At the same time, it is difficult to investigate this variability by experiments alone. A recent modelling and simulation approach, known as population of models (POM), allows this exploration to take place by building a mathematical model consisting of multiple parameter sets calibrated against experimental data. However, finding such sets within a high-dimensional parameter space of complex electrophysiological models is computationally challenging. By placing the POM approach within a statistical framework, we develop a novel and efficient algorithm based on sequential Monte Carlo (SMC). We compare the SMC approach with Latin hypercube sampling (LHS), a method commonly adopted in the literature for obtaining the POM, in terms of efficiency and output variability in the presence of a drug block through an in-depth investigation via the Beeler-Reuter cardiac electrophysiological model. We show improved efficiency for SMC that produces similar responses to LHS when making out-of-sample predictions in the presence of a simulated drug block. Finally, we show the performance of our approach on a complex atrial electrophysiological model, namely the Courtemanche-Ramirez-Nattel model.

Three months' treatment with cyclophosphamide, VP-16-213 followed by methotrexate and thoracic radiotherapy for small cell lung cancer.

One hundred eleven patients with inoperable but limited-stage small cell lung cancer were treated with three courses of cyclophosphamide (1.5, 2.5, and 3.5 g/m2, respectively) and VP-16-213 followed by methotrexate and thoracic radiotherapy. The total duration of treatment was 3 months. Patients were included who had pleural effusions, contralateral neck nodes, and bone marrow infiltration. The complete response (CR) rate was 56%, the majority confirmed by repeat bronchoscopy, with an 81% overall response rate. The minimum follow-up was 14 months. Median survival for all 111 patients was 11 months and 14 months (1-34+) for complete responders; the median survival was also 11 months for the 91 patients with conventional limited-stage disease, although 15 of the 19 patients alive at 14 months or more were from this subpopulation. There was no significant difference in the survival of those CR patients whose response was confirmed bronchoscopically and patients whose CR was assessed only radiologically and clinically. Forty-four patients with leukopenia (less than 1000 cells/microliter) received intravenous antibiotics for malaise and suspected infection. Close monitoring between treatments and direct access of patients to the hospital was encouraged. The majority of patients improved symptomatically as assessed by Karnofsky and Respiratory scores. These results support the view that short but intensive treatment without long-term or maintenance chemotherapy is beneficial.