The Future of Drug Development: The Economics of Pharmacogenomics

This paper models how the evolving field of pharmacogenomics (PG), which is the science of using genomic markers to predict drug response, may impact drug development times, attrition rates, costs, and the future returns to research and development (R&D). While there still remains an abundance of uncertainty around how PG will impact the future landscape of pharmaceutical and biological R&D, we identify several likely outcomes. We conclude PG has the potential to significantly reduce both expected drug development costs (via higher probabilities of technical success, shorter clinical development times, and smaller clinical trials) and returns. The impact PG has on expected returns is partially mitigated by higher equilibrium prices, expedited product launches, and longer effective patent lives. Our conclusions are, of course, accompanied by numerous caveats.

Use of Multivariate Techniques to Validate and Improved the Current USAF Pilot Candidate Selection Model

The Pilot Candidate Selection Method (PCSM) seeks to ensure the highest possible probability of success at UPT. PCSM applies regression weights to a candidate\u27s Air Force Officer Qualification Test (AFOQT) Pilot composite score, self-reported flying hours, and five Basic Attributes Test (BAT) score composites. PCSM scores range between 0 and 99 and is interpreted as a candidate\u27s probability of passing UPT. The goal of this study is to apply multivariate data analysis techniques to validate PCSM and determine appropriate changes to the model\u27s weights. Performance of the updated weights is compared to the current PCSM model via Receiver Operating Curves (ROC). In addition, two independent models are developed using multi-layer perceptron neural networks and discriminant analysis. Both linear and logistic regression is used to investigate possible updates to PCSM\u27s current linear regression weights. An independent test set is used to estimate the generalized performance of the regressions and independent models. Validation of the current PCSM model demonstrated in the first phase of this research is enhanced by the fact that PCSM outperforms all other models developed in the research

A normal form for excitable media

We present a normal form for travelling waves in one-dimensional excitable media in form of a differential delay equation. The normal form is built around the well-known saddle-node bifurcation generically present in excitable media. Finite wavelength effects are captured by a delay. The normal form describes the behaviour of single pulses in a periodic domain and also the richer behaviour of wave trains. The normal form exhibits a symmetry preserving Hopf bifurcation which may coalesce with the saddle-node in a Bogdanov-Takens point, and a symmetry breaking spatially inhomogeneous pitchfork bifurcation. We verify the existence of these bifurcations in numerical simulations. The parameters of the normal form are determined and its predictions are tested against numerical simulations of partial differential equation models of excitable media with good agreement.Comment: 22 pages, accepted for publication in Chao

Instability and spatiotemporal rheochaos in a shear-thickening fluid model

We model a shear-thickening fluid that combines a tendency to form inhomogeneous, shear-banded flows with a slow relaxational dynamics for fluid microstructure. The interplay between these factors gives rich dynamics, with periodic regimes (oscillating bands, travelling bands, and more complex oscillations) and spatiotemporal rheochaos. These phenomena, arising from constitutive nonlinearity not inertia, can occur even when the steady-state flow curve is monotonic. Our model also shows rheochaos in a low-dimensional truncation where sharply defined shear bands cannot form

Pulse propagation in discrete systems of coupled excitable cells

Propagation of pulses in myelinated fibers may be described by appropriate solutions of spatially discrete FitzHugh-Nagumo systems. In these systems, propagation failure may occur if either the coupling between nodes is not strong enough or the recovery is too fast. We give an asymptotic construction of pulses for spatially discrete FitzHugh-Nagumo systems which agrees well with numerical simulations and discuss evolution of initial data into pulses and pulse generation at a boundary. Formulas for the speed and length of pulses are also obtained.Comment: 16 pages, 10 figures, to appear in SIAM J. Appl. Mat

Wave trains, self-oscillations and synchronization in discrete media

We study wave propagation in networks of coupled cells which can behave as excitable or self-oscillatory media. For excitable media, an asymptotic construction of wave trains is presented. This construction predicts their shape and speed, as well as the critical coupling and the critical separation of time scales for propagation failure. It describes stable wave train generation by repeated firing at a boundary. In self-oscillatory media, wave trains persist but synchronization phenomena arise. An equation describing the evolution of the oscillator phases is derived.Comment: to appear in Physica D: Nonlinear Phenomen

Universal behavior in populations composed of excitable and self-oscillatory elements

We study the robustness of self-sustained oscillatory activity in a globally coupled ensemble of excitable and oscillatory units. The critical balance to achieve collective self-sustained oscillations is analytically established. We also report a universal scaling function for the ensemble's mean frequency. Our results extend the framework of the `Aging Transition' [Phys. Rev. Lett. 93, 104101 (2004)] including a broad class of dynamical systems potentially relevant in biology.Comment: 4 pages; Changed titl

Spontaneous spiking in an autaptic Hodgkin-Huxley set up

The effect of intrinsic channel noise is investigated for the dynamic response of a neuronal cell with a delayed feedback loop. The loop is based on the so-called autapse phenomenon in which dendrites establish not only connections to neighboring cells but as well to its own axon. The biophysical modeling is achieved in terms of a stochastic Hodgkin-Huxley model containing such a built in delayed feedback. The fluctuations stem from intrinsic channel noise, being caused by the stochastic nature of the gating dynamics of ion channels. The influence of the delayed stimulus is systematically analyzed with respect to the coupling parameter and the delay time in terms of the interspike interval histograms and the average interspike interval. The delayed feedback manifests itself in the occurrence of bursting and a rich multimodal interspike interval distribution, exhibiting a delay-induced reduction of the spontaneous spiking activity at characteristic frequencies. Moreover, a specific frequency-locking mechanism is detected for the mean interspike interval.Comment: 8 pages, 10 figure