The paper discusses variable selection as used in large metabolomic studies, exemplified by mouse urinary gas chromatography of 441 mice in three experiments to detect the influence of age, diet and stress on their chemosignal. Partial Least Squares Discriminant Analysis (PLS-DA) was applied to obtain class models, using a procedure of 20,000 iterations including the bootstrap for model optimisation and random splits into test and training sets for validation. Variables are selected using PLS regression coefficients on the training set using an optimised number of components obtained from the bootstrap. The variables are ranked in order of significance and the overall optimal variables are selected as those that appear as highly significant over 100 different test and training set splits. Cost benefit analysis of performing the model on a reduced number of variables is also illustrated. This paper provides a strategy for properly validated methods for determining which variables are most significant for discriminating between two groups in large metabolomic datasets avoiding the common pitfall of overfitting if variables are selected on a combined training and test set, and also taking into account that different variables may be selected each time the samples are split into training and test sets using iterative procedures.
The development and optimization of many new drug therapies requires long-term local delivery with controlled, but variable dosage. Current methods for chronic drug delivery have limited utility because they either cannot deliver drugs locally to a specific organ or tissue, do not permit changes in delivery rate in situ, or cannot be used in clinical trials in an untethered, wearable configuration. Here, we describe a small, self-contained system for liquid-phase drug delivery. This system enables studies lasting several months and infusion rates can be programmed and modified remotely. A commercial miniature pump is integrated with microfabricated components to generate ultralow flow rates and stroke volumes. Solutions are delivered in pulses as small as 370 nL, with pulses delivered at any interval of 1 min or longer. A unique feature of the system is the ability to infuse and immediately withdraw liquid, resulting in zero net volume transfer while compounds are exchanged by mixing and diffusion with endogenous fluid. We present in vitro results demonstrating repeatability of the delivered pulse volume for nearly 3 months. Furthermore, we present in vivo results in an otology application, infusing into the cochlea of a guinea pig a glutamate receptor antagonist, which causes localized and reversible changes in auditory sensitivity.
Background: Direct delivery of drugs and other agents into the inner ear will be important for many emerging therapies, including the treatment of degenerative disorders and guiding regeneration. Methods: We have taken a microfluidics/MEMS (MicroElectroMechanical Systems) technology approach to develop a fully implantable reciprocating inner-ear drug-delivery system capable of timed and sequenced delivery of agents directly into perilymph of the cochlea. Iterations of the device were tested in guinea pigs to determine the flow characteristics required for safe and effective delivery. For these tests, we used the glutamate receptor blocker DNQX, which alters auditory nerve responses but not cochlear distortion product otoacoustic emissions. Results: We have demonstrated safe and effective delivery of agents into the scala tympani. Equilibration of the drug in the basal turn occurs rapidly (within tens of minutes) and is dependent on reciprocating flow parameters. Conclusion: We have described a prototype system for the direct delivery of drugs to the inner ear that has the potential to be a fully implantable means for safe and effective treatment of hearing loss and other diseases.
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