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Application of SPLINDID, a Semiparametric, Model-Based Method for Pharmacogenomic Modeling of mRNA Dynamics

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Purpose

This study was conducted to evaluate the applicability of SPLINDID, a semiparametric, model-based approach for obtaining transcription rates from the pharmacodynamics of mRNA expression.

Methods

A nonparametric exponential cubic spline function was used to obtain the transcription rate profile and the dynamics of mRNA expression was fitted using compartmental approaches. The transcription rate profile and mRNA degradation parameter was estimated using maximum likelihood method of ADAPT II software.

Results

Data sets containing noise for mRNA levels were simulated for four diverse pharmaceutically relevant conditions: receptor nonlinearity, a model in which the variant mRNAs differing in mRNA degradation constants were transcribed and for a minimal model of the cell cycle. SPLINDID was able to fit the data sets and accurately recapitulate the transcription rate profiles normalized to the mRNA degradation rate constants. The model was also challenged using experimental data containing time profiles of cell-cycle-regulated genes.

Conclusions

The SPLINDID approach is flexible in capturing complicated/complex mRNA profiles that are encountered in many experimental data sets.

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Acknowledgments

This work was supported in part by grants from the Kapoor Foundation, National Science Foundation (Research Grant 0234895) and the National Institutes of Health (P20-GM 067650).

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, State University of New York at Buffalo, 543 Cooke Hall, Buffalo, New York, 14260-1200, USA

    Kavitha Bhasi, Alan Forrest & Murali Ramanathan

Authors
  1. Kavitha Bhasi
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  2. Alan Forrest
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  3. Murali Ramanathan
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Correspondence to Murali Ramanathan.

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Bhasi, K., Forrest, A. & Ramanathan, M. Application of SPLINDID, a Semiparametric, Model-Based Method for Pharmacogenomic Modeling of mRNA Dynamics. Pharm Res 23, 663–669 (2006). https://doi.org/10.1007/s11095-006-9747-1

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  • DOI: https://doi.org/10.1007/s11095-006-9747-1

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