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1.  Best Practices for Scientific Computing 
PLoS Biology  2014;12(1):e1001745.
We describe a set of best practices for scientific software development, based on research and experience, that will improve scientists' productivity and the reliability of their software.
doi:10.1371/journal.pbio.1001745
PMCID: PMC3886731  PMID: 24415924
2.  Bootstrap Aggregating of Alternating Decision Trees to Detect Sets of SNPs that Associate with Disease 
Genetic epidemiology  2012;36(2):99-106.
Complex genetic disorders are a result of a combination of genetic and non-genetic factors, all potentially interacting. Machine learning methods hold the potential to identify multi-locus and environmental associations thought to drive complex genetic traits. Decision trees, a popular machine learning technique, offer a computationally low complexity algorithm capable of detecting associated sets of SNPs of arbitrary size, including modern genome-wide SNP scans. However, interpretation of the importance of an individual SNP within these trees can present challenges.
We present a new decision tree algorithm denoted as Bagged Alternating Decision Trees (BADTrees) that is based on identifying common structural elements in a bootstrapped set of ADTrees. The algorithm is order nk2, where n is the number of SNPs considered and k is the number of SNPs in the tree constructed. Our simulation study suggests that BADTrees have higher power and lower type I error rates than ADTrees alone and comparable power with lower type I error rates compared to logistic regression. We illustrate the application of these data using simulated data as well as from the Lupus Large Association Study 1 (7822 SNPs in 3548 individuals). Our results suggest that BADTrees holds promise as a low computational order algorithm for detecting complex combinations of SNP and environmental factors associated with disease.
doi:10.1002/gepi.21608
PMCID: PMC3769952  PMID: 22851473
Machine Learning; Genetic Association; Gene-Gene Interaction; Multi-locus Models
3.  Genetic Analyses of Interferon Pathway-Related Genes Reveals Multiple New Loci Associated with Systemic Lupus Erythematosus (SLE) 
Arthritis and rheumatism  2011;63(7):2049-2057.
Objective
The overexpression of interferon (IFN)-inducible genes is a prominent feature of SLE, serves as a marker for active and more severe disease, and is also observed in other autoimmune and inflammatory conditions. The genetic variations responsible for sustained activation of IFN responsive genes are unknown.
Methods
We systematically evaluated association of SLE with a total of 1,754 IFN-pathway related genes, including IFN-inducible genes known to be differentially expressed in SLE patients and their direct regulators. We performed a three-stage design where two cohorts (total n=939 SLE cases, 3,398 controls) were analyzed independently and jointly for association with SLE, and the results were adjusted for the number of comparisons.
Results
A total of 16,137 SNPs passed all quality control filters of which 316 demonstrated replicated association with SLE in both cohorts. Nine variants were further genotyped for confirmation in an average of 1,316 independent SLE cases and 3,215 independent controls. Association with SLE was confirmed for several genes, including the transmembrane receptor CD44 (rs507230, P = 3.98×10−12), cytokine pleiotrophin (PTN) (rs919581, P = 5.38×10−04), the heat-shock DNAJA1 (rs10971259, P = 6.31×10−03), and the nuclear import protein karyopherin alpha 1 (KPNA1) (rs6810306, P = 4.91×10−02).
Conclusion
This study expands the number of candidate genes associated with SLE and highlights the potential of pathway-based approaches for gene discovery. Identification of the causal alleles will help elucidate the molecular mechanisms responsible for activation of the IFN system in SLE.
doi:10.1002/art.30356
PMCID: PMC3128183  PMID: 21437871
4.  Imaging Drug Delivery to Skin with Stimulated Raman Scattering Microscopy 
Molecular pharmaceutics  2011;8(3):969-975.
Efficient drug delivery to the skin is essential for the treatment of major dermatologic diseases, such as eczema, psoriasis and acne. However, many compounds penetrate the skin barrier poorly and require optimized formulations to ensure their bioavailability. Here, stimulated Raman scattering (SRS) microscopy, a recently-developed, label-free chemical imaging tool, is used to acquire high resolution images of multiple chemical components of a topical formulation as it penetrates into mammalian skin. This technique uniquely provides label-free, non-destructive, three-dimensional images with high spatiotemporal resolution. It reveals novel features of (trans)dermal drug delivery in the tissue environment: different rates of drug penetration via hair follicles as compared to the intercellular pathway across the stratum corneum are directly observed, and the precipitation of drug crystals on the skin surface is visualized after the percutaneous penetration of the co-solvent excipient in the formulation. The high speed three-dimensional imaging capability of SRS thus reveals features that cannot be seen with other techniques, providing both kinetic information and mechanistic insight into the (trans)dermal drug delivery process.
doi:10.1021/mp200122w
PMCID: PMC3109166  PMID: 21548600
Skin; topical drug delivery; stimulated Raman scattering microscopy; skin penetration pathways; dermatopharmacokinetics
5.  Quantitative structure-permeation relationship for iontophoretic transport across the skin 
The objective was to relate the efficiency of a charged drug to carry current across the skin during iontophoresis to its structural and/or physicochemical properties. The corollary was the establishment of a predictive relationship useful to predict the feasibility of iontophoretic drug delivery, and for the selection and optimization of drug candidates for this route of administration. A dataset of 16 cations, for which iontophoretic fluxes have been measured under identical conditions, with no competition from exogenous co-ions, was compiled. Maximum transport numbers correlated with ion mobilities and decreased with ionic size, the dependence indicating that the electromigration mechanism of iontophoresis would become negligible for drugs of hydrodynamic radius greater than about 8Å. Validation of the model was demonstrated by successfully predicting the transport numbers of three structurally distinct dipeptides, the iontophoretic data for which had been determined under distinctly different experimental conditions. Finally, for the “training” set of cations, a strong linear dependence between their transport numbers in skin and those in aqueous solution was demonstrated; the former were larger by approximately a factor of 1.4 consistent with skin’s cation permselectivity. In conclusion, this research offers a practical contribution to the development of a predictive structure-transport model of iontophoresis.
doi:10.1016/j.jconrel.2007.07.004
PMCID: PMC2082109  PMID: 17707106
iontophoresis; skin; transport number; conductivity; structure-transport relationship
6.  In Vivo Methods for the Assessment of Topical Drug Bioavailability 
Pharmaceutical Research  2007;25(1):87-103.
This paper reviews some current methods for the in vivo assessment of local cutaneous bioavailability in humans after topical drug application. After an introduction discussing the importance of local drug bioavailability assessment and the limitations of model-based predictions, the focus turns to the relevance of experimental studies. The available techniques are then reviewed in detail, with particular emphasis on the tape stripping and microdialysis methodologies. Other less developed techniques, including the skin biopsy, suction blister, follicle removal and confocal Raman spectroscopy techniques are also described.
doi:10.1007/s11095-007-9429-7
PMCID: PMC2217624  PMID: 17985216
cutaneous bioavailability; cutaneous drug concentration; dermatopharmacokinetics; microdialysis; tape stripping
7.  WebMOTIFS: automated discovery, filtering and scoring of DNA sequence motifs using multiple programs and Bayesian approaches 
Nucleic Acids Research  2007;35(Web Server issue):W217-W220.
WebMOTIFS provides a web interface that facilitates the discovery and analysis of DNA-sequence motifs. Several studies have shown that the accuracy of motif discovery can be significantly improved by using multiple de novo motif discovery programs and using randomized control calculations to identify the most significant motifs or by using Bayesian approaches. WebMOTIFS makes it easy to apply these strategies. Using a single submission form, users can run several motif discovery programs and score, cluster and visualize the results. In addition, the Bayesian motif discovery program THEME can be used to determine the class of transcription factors that is most likely to regulate a set of sequences. Input can be provided as a list of gene or probe identifiers. Used with the default settings, WebMOTIFS accurately identifies biologically relevant motifs from diverse data in several species. WebMOTIFS is freely available at http://fraenkel.mit.edu/webmotifs.
doi:10.1093/nar/gkm376
PMCID: PMC1933171  PMID: 17584794
8.  Shell shock 
PMCID: PMC1079480  PMID: 15121824
10.  Recovery of human skin impedance in vivo after lontophoresis: Effect of metal ions 
AAPS PharmSci  2000;2(3):38-44.
The objective of this study was to investigate the effect of the counter-ion (cation) on the recovery of human skin impedance after iontophoresis in vivo. A series of metal chloride aqueous solutions (NaCl, KCl, CaCl2, and MgCl2) was investigated: first at the same concentration (133 mmol/L) and then at the same ionic strength as a NaCl solution at 133 mmol/L. The influence of hydration alone was also examined as a control. The recovery of human skin impedance was followed in the frequency range 1–1,000 Hz, over a 30-minute period after iontophoresis during which 3 impedance spectra were recorded. The results revealed that at t=30 minutes post-iontophoresis, skin impedance was approximately 3 times greater than the value immediately after the cessation of current passage. However, the results showed that the nature of the cation had no effect on recovery, regardless of whether the ions were at the same concentration or at an equivalent ionic strength. A simple parallel RC-equivalent circuit model for skin was used to determine the resistive (R) and capacitive (C) contributions to skin impedance. An analysis of variance on the calculated R and C values did not show any differences between the electrolytes used at the 2 different ionic strengths.
doi:10.1208/ps020323
PMCID: PMC2761134  PMID: 11741239

Results 1-10 (10)