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Fulltext clrDV: a differential variability test for RNA-Seq data based on the skew-normal distribution

Li H, Khang TF

PeerJ, 2023;11:e16126.
PMID: 37790621 DOI: 10.7717/peerj.16126

BACKGROUND: Pathological conditions may result in certain genes having expression variance that differs markedly from that of the control. Finding such genes from gene expression data can provide invaluable candidates for therapeutic intervention. Under the dominant paradigm for modeling RNA-Seq gene counts using the negative binomial model, tests of differential variability are challenging to develop, owing to dependence of the variance on the mean.
METHODS: Here, we describe clrDV, a statistical method for detecting genes that show differential variability between two populations. We present the skew-normal distribution for modeling gene-wise null distribution of centered log-ratio transformation of compositional RNA-seq data.
RESULTS: Simulation results show that clrDV has false discovery rate and probability of Type II error that are on par with or superior to existing methodologies. In addition, its run time is faster than its closest competitors, and remains relatively constant for increasing sample size per group. Analysis of a large neurodegenerative disease RNA-Seq dataset using clrDV successfully recovers multiple gene candidates that have been reported to be associated with Alzheimer's disease.
Fulltext Getting the most out of RNA-seq data analysis

Khang TF, Lau CY

PeerJ, 2015;3:e1360.
PMID: 26539333 DOI: 10.7717/peerj.1360

Background. A common research goal in transcriptome projects is to find genes that are differentially expressed in different phenotype classes. Biologists might wish to validate such gene candidates experimentally, or use them for downstream systems biology analysis. Producing a coherent differential gene expression analysis from RNA-seq count data requires an understanding of how numerous sources of variation such as the replicate size, the hypothesized biological effect size, and the specific method for making differential expression calls interact. We believe an explicit demonstration of such interactions in real RNA-seq data sets is of practical interest to biologists. Results. Using two large public RNA-seq data sets-one representing strong, and another mild, biological effect size-we simulated different replicate size scenarios, and tested the performance of several commonly-used methods for calling differentially expressed genes in each of them. We found that, when biological effect size was mild, RNA-seq experiments should focus on experimental validation of differentially expressed gene candidates. Importantly, at least triplicates must be used, and the differentially expressed genes should be called using methods with high positive predictive value (PPV), such as NOISeq or GFOLD. In contrast, when biological effect size was strong, differentially expressed genes mined from unreplicated experiments using NOISeq, ASC and GFOLD had between 30 to 50% mean PPV, an increase of more than 30-fold compared to the cases of mild biological effect size. Among methods with good PPV performance, having triplicates or more substantially improved mean PPV to over 90% for GFOLD, 60% for DESeq2, 50% for NOISeq, and 30% for edgeR. At a replicate size of six, we found DESeq2 and edgeR to be reasonable methods for calling differentially expressed genes at systems level analysis, as their PPV and sensitivity trade-off were superior to the other methods'. Conclusion. When biological effect size is weak, systems level investigation is not possible using RNAseq data, and no meaningful result can be obtained in unreplicated experiments. Nonetheless, NOISeq or GFOLD may yield limited numbers of gene candidates with good validation potential, when triplicates or more are available. When biological effect size is strong, NOISeq and GFOLD are effective tools for detecting differentially expressed genes in unreplicated RNA-seq experiments for qPCR validation. When triplicates or more are available, GFOLD is a sharp tool for identifying high confidence differentially expressed genes for targeted qPCR validation; for downstream systems level analysis, combined results from DESeq2 and edgeR are useful.
Fulltext On the classification of simple and complex biological images using Krawtchouk moments and Generalized pseudo-Zernike moments: a case study with fly wing images and breast cancer mammograms

Goh JY, Khang TF

PeerJ Comput Sci, 2021;7:e698.
PMID: 34604523 DOI: 10.7717/peerj-cs.698

In image analysis, orthogonal moments are useful mathematical transformations for creating new features from digital images. Moreover, orthogonal moment invariants produce image features that are resistant to translation, rotation, and scaling operations. Here, we show the result of a case study in biological image analysis to help researchers judge the potential efficacy of image features derived from orthogonal moments in a machine learning context. In taxonomic classification of forensically important flies from the Sarcophagidae and the Calliphoridae family (n = 74), we found the GUIDE random forests model was able to completely classify samples from 15 different species correctly based on Krawtchouk moment invariant features generated from fly wing images, with zero out-of-bag error probability. For the more challenging problem of classifying breast masses based solely on digital mammograms from the CBIS-DDSM database (n = 1,151), we found that image features generated from the Generalized pseudo-Zernike moments and the Krawtchouk moments only enabled the GUIDE kernel model to achieve modest classification performance. However, using the predicted probability of malignancy from GUIDE as a feature together with five expert features resulted in a reasonably good model that has mean sensitivity of 85%, mean specificity of 61%, and mean accuracy of 70%. We conclude that orthogonal moments have high potential as informative image features in taxonomic classification problems where the patterns of biological variations are not overly complex. For more complicated and heterogeneous patterns of biological variations such as those present in medical images, relying on orthogonal moments alone to reach strong classification performance is unrealistic, but integrating prediction result using them with carefully selected expert features may still produce reasonably good prediction models.
Fulltext Safety of Brilliant Blue G

Fong KC, Ooi YL, Khang TF

Eye (Lond), 2014 Sep;28(9):1148.
PMID: 24875224 DOI: 10.1038/eye.2014.123
Fulltext A phylogenomic approach to bacterial subspecies classification: proof of concept in Mycobacterium abscessus

Tan JL, Khang TF, Ngeow YF, Choo SW

BMC Genomics, 2013;14:879.
PMID: 24330254 DOI: 10.1186/1471-2164-14-879

Mycobacterium abscessus is a rapidly growing mycobacterium that is often associated with human infections. The taxonomy of this species has undergone several revisions and is still being debated. In this study, we sequenced the genomes of 12 M. abscessus strains and used phylogenomic analysis to perform subspecies classification.
An age-adjusted seroprevalence study of Toxoplasma antibody in a Malaysian ophthalmology unit

Singh S, Khang TF, Andiappan H, Nissapatorn V, Subrayan V

Trans R Soc Trop Med Hyg, 2012 May;106(5):322-6.
PMID: 22480791 DOI: 10.1016/j.trstmh.2012.01.009

Toxoplasma gondii is a public health risk in developing countries, especially those located in the tropics. Widespread infection may inflict a substantial burden on state resources, as patients can develop severe neurological defects and ocular diseases that result in lifelong loss of economic independence. We tested sera for IgG antibody from 493 eye patients in Malaysia. Overall age-adjusted seroprevalence was estimated to be 25% (95% CI: [21%, 29%]). We found approximately equal age-adjusted seroprevalence in Chinese (31%; 95% CI: [25%, 38%]) and Malays (29%; 95% CI: [21%, 36%]), followed by Indians (19%; 95% CI: [13%, 25%]). A logistic regression of the odds for T. gondii seroprevalence against age, gender, ethnicity and the occurrence of six types of ocular diseases showed that only age and ethnicity were significant predictors. The odds for T. gondii seroprevalence were 2.7 (95% CI for OR: [1.9, 4.0]) times higher for a patient twice as old as the other, with ethnicity held constant. In Malays, we estimated the odds for T. gondii seroprevalence to be 2.9 (95% CI for OR: [1.8, 4.5]) times higher compared to non-Malays, with age held constant. Previous studies of T. gondii seroprevalence in Malaysia did not explicitly adjust for age, rendering comparisons difficult. Our study highlights the need to adopt a more rigorous epidemiological approach in monitoring T. gondii seroprevalence in Malaysia.
Fulltext Agreement analysis of LENSTAR with other techniques of biometry

Jasvinder S, Khang TF, Sarinder KK, Loo VP, Subrayan V

Eye (Lond), 2011 Jun;25(6):717-24.
PMID: 21394115 DOI: 10.1038/eye.2011.28

To assess the agreement of the optical low-coherence reflectometry (OLCR) device LENSTAR LS900 with partial coherence interferometry (PCI) device IOLMaster and applanation and immersion ultrasound biometry.
Fulltext The structural effect of intravitreal Brilliant blue G and Indocyanine green in rats eyes

Ooi YL, Khang TF, Naidu M, Fong KC

Eye (Lond), 2013 Mar;27(3):425-31.
PMID: 23196646 DOI: 10.1038/eye.2012.260

To compare the potential retinal toxicity of two commercially Brilliant blue G dyes (Brilliant Peel and Ocublue Plus) and Indocyanine green (ICG) at usual clinical concentration.
Gross mismatch between thermal tolerances and environmental temperatures in a tropical freshwater snail: climate warming and evolutionary implications

Polgar G, Khang TF, Chua T, Marshall DJ

J Therm Biol, 2015 Jan;47:99-108.
PMID: 25526660 DOI: 10.1016/j.jtherbio.2014.11.009

The relationship between acute thermal tolerance and habitat temperature in ectotherm animals informs about their thermal adaptation and is used to assess thermal safety margins and sensitivity to climate warming. We studied this relationship in an equatorial freshwater snail (Clea nigricans), belonging to a predominantly marine gastropod lineage (Neogastropoda, Buccinidae). We found that tolerance of heating and cooling exceeded average daily maximum and minimum temperatures, by roughly 20°C in each case. Because habitat temperature is generally assumed to be the main selective factor acting on the fundamental thermal niche, the discordance between thermal tolerance and environmental temperature implies trait conservation following 'in situ' environmental change, or following novel colonisation of a thermally less-variable habitat. Whereas heat tolerance could relate to an historical association with the thermally variable and extreme marine intertidal fringe zone, cold tolerance could associate with either an ancestral life at higher latitudes, or represent adaptation to cooler, higher-altitudinal, tropical lotic systems. The broad upper thermal safety margin (difference between heat tolerance and maximum environmental temperature) observed in this snail is grossly incompatible with the very narrow safety margins typically found in most terrestrial tropical ectotherms (insects and lizards), and hence with the emerging prediction that tropical ectotherms, are especially vulnerable to environmental warming. A more comprehensive understanding of climatic vulnerability of animal ectotherms thus requires greater consideration of taxonomic diversity, ecological transition and evolutionary history.
Random forests for predicting species identity of forensically important blow flies (Diptera: Calliphoridae) and flesh flies (Diptera: Sarcophagidae) using geometric morphometric data: Proof of concept

Khang TF, Mohd Puaad NAD, Teh SH, Mohamed Z

J Forensic Sci, 2021 May;66(3):960-970.
PMID: 33438785 DOI: 10.1111/1556-4029.14655

Wing shape variation has been shown to be useful for delineating forensically important fly species in two Diptera families: Calliphoridae and Sarcophagidae. Compared to DNA-based identification, the cost of geometric morphometric data acquisition and analysis is relatively much lower because the tools required are basic, and stable softwares are available. However, to date, an explicit demonstration of using wing geometric morphometric data for species identity prediction in these two families remains lacking. Here, geometric morphometric data from 19 homologous landmarks on the left wing of males from seven species of Calliphoridae (n = 55), and eight species of Sarcophagidae (n = 40) were obtained and processed using Generalized Procrustes Analysis. Allometric effect was removed by regressing centroid size (in log10 ) against the Procrustes coordinates. Subsequently, principal component analysis of the allometry-adjusted Procrustes variables was done, with the first 15 principal components used to train a random forests model for species prediction. Using a real test sample consisting of 33 male fly specimens collected around a human corpse at a crime scene, the estimated percentage of concordance between species identities predicted using the random forests model and those inferred using DNA-based identification was about 80.6% (approximate 95% confidence interval = [68.9%, 92.2%]). In contrast, baseline concordance using naive majority class prediction was 36.4%. The results provide proof of concept that geometric morphometric data has good potential to complement morphological and DNA-based identification of blow flies and flesh flies in forensic work.
Fulltext CORNAS: coverage-dependent RNA-Seq analysis of gene expression data without biological replicates

Low JZB, Khang TF, Tammi MT

BMC Bioinformatics, 2017 12 28;18(Suppl 16):575.
PMID: 29297307 DOI: 10.1186/s12859-017-1974-4

BACKGROUND: In current statistical methods for calling differentially expressed genes in RNA-Seq experiments, the assumption is that an adjusted observed gene count represents an unknown true gene count. This adjustment usually consists of a normalization step to account for heterogeneous sample library sizes, and then the resulting normalized gene counts are used as input for parametric or non-parametric differential gene expression tests. A distribution of true gene counts, each with a different probability, can result in the same observed gene count. Importantly, sequencing coverage information is currently not explicitly incorporated into any of the statistical models used for RNA-Seq analysis.
RESULTS: We developed a fast Bayesian method which uses the sequencing coverage information determined from the concentration of an RNA sample to estimate the posterior distribution of a true gene count. Our method has better or comparable performance compared to NOISeq and GFOLD, according to the results from simulations and experiments with real unreplicated data. We incorporated a previously unused sequencing coverage parameter into a procedure for differential gene expression analysis with RNA-Seq data.
CONCLUSIONS: Our results suggest that our method can be used to overcome analytical bottlenecks in experiments with limited number of replicates and low sequencing coverage. The method is implemented in CORNAS (Coverage-dependent RNA-Seq), and is available at https://github.com/joel-lzb/CORNAS .
Diverse impacts of red palm olein, extra virgin coconut oil and extra virgin olive oil on cardiometabolic risk markers in individuals with central obesity: a randomised trial

Teng KT, Loganathan R, Chew BH, Khang TF

Eur J Nutr, 2024 Feb 19.
PMID: 38372798 DOI: 10.1007/s00394-024-03338-6

PURPOSE: Dietary fats with an abundance of phytonutrients have garnered public attention beyond fatty acids per se. This study was set to investigate the impact of consuming diets with red palm olein (RPOO), extra virgin coconut oil (EVCO) and extra virgin olive oil (EVOO, as a control) on cardiometabolic risk biomarkers and lipid profile.
METHODS: We recruited a total of 156 individuals with central obesity, aged 25-45 years, with waist circumference ≥ 90 cm for men and ≥ 80 cm for women in a parallel single-blind 3-arm randomised controlled trial. The participants consumed isocaloric diets (~ 2400 kcal) enriched with respective test fats (RPOO, EVCO or EVOO) for a 12-week duration.
RESULTS: The mean of the primary outcome plasma high sensitivity C-reactive protein was statistically similar between the three diets after a 12-week intervention. EVOO resulted in significantly lower mean LDL cholesterol compared with RPOO and EVCO, despite similar effects on LDL and HDL cholesterol subfractions. The RPOO diet group showed elevated mean [Formula: see text] and [Formula: see text]-carotenes levels compared with EVCO and EVOO diet groups (P
Fulltext Monogenean anchor morphometry: systematic value, phylogenetic signal, and evolution

Khang TF, Soo OY, Tan WB, Lim LH

PeerJ, 2016;4:e1668.
PMID: 26966649 DOI: 10.7717/peerj.1668

Background. Anchors are one of the important attachment appendages for monogenean parasites. Common descent and evolutionary processes have left their mark on anchor morphometry, in the form of patterns of shape and size variation useful for systematic and evolutionary studies. When combined with morphological and molecular data, analysis of anchor morphometry can potentially answer a wide range of biological questions. Materials and Methods. We used data from anchor morphometry, body size and morphology of 13 Ligophorus (Monogenea: Ancyrocephalidae) species infecting two marine mugilid (Teleostei: Mugilidae) fish hosts: Moolgarda buchanani (Bleeker) and Liza subviridis (Valenciennes) from Malaysia. Anchor shape and size data (n = 530) were generated using methods of geometric morphometrics. We used 28S rRNA, 18S rRNA, and ITS1 sequence data to infer a maximum likelihood phylogeny. We discriminated species using principal component and cluster analysis of shape data. Adams's K mult was used to detect phylogenetic signal in anchor shape. Phylogeny-correlated size and shape changes were investigated using continuous character mapping and directional statistics, respectively. We assessed morphological constraints in anchor morphometry using phylogenetic regression of anchor shape against body size and anchor size. Anchor morphological integration was studied using partial least squares method. The association between copulatory organ morphology and anchor shape and size in phylomorphospace was used to test the Rohde-Hobbs hypothesis. We created monogeneaGM, a new R package that integrates analyses of monogenean anchor geometric morphometric data with morphological and phylogenetic data. Results. We discriminated 12 of the 13 Ligophorus species using anchor shape data. Significant phylogenetic signal was detected in anchor shape. Thus, we discovered new morphological characters based on anchor shaft shape, the length between the inner root point and the outer root point, and the length between the inner root point and the dent point. The species on M. buchanani evolved larger, more robust anchors; those on L. subviridis evolved smaller, more delicate anchors. Anchor shape and size were significantly correlated, suggesting constraints in anchor evolution. Tight integration between the root and the point compartments within anchors confirms the anchor as a single, fully integrated module. The correlation between male copulatory organ morphology and size with anchor shape was consistent with predictions from the Rohde-Hobbs hypothesis. Conclusions. Monogenean anchors are tightly integrated structures, and their shape variation correlates strongly with phylogeny, thus underscoring their value for systematic and evolutionary biology studies. Our MonogeneaGM R package provides tools for researchers to mine biological insights from geometric morphometric data of speciose monogenean genera.
Fulltext Spectral-domain optical coherence tomography evaluation of postoperative cystoid macular oedema following phacoemulsification with intraoperative complication

Khaw KW, Lam HH, Khang TF, Wan Ab Kadir AJ, Subrayan V

BMC Ophthalmol, 2014;14:16.
PMID: 24533465 DOI: 10.1186/1471-2415-14-16

To report the rate of cystoid macular oedema (CMO) as detected by spectral-domain optical coherence tomography (SD-OCT) after intraoperative complication during phacoemulsification. The secondary objectives include comparing mean macular thickness and best-corrected visual acuity (BCVA) between those who developed postoperative CMO against those who did not.
Comparative analysis of viral genomes from acute and chronic hepatitis B reveals novel variants associated with a lower rate of chronicity

Chook JB, Ngeow YF, Khang TF, Ng KP, Tiang YP, Mohamed R

J Med Virol, 2013 Mar;85(3):419-24.
PMID: 23297244 DOI: 10.1002/jmv.23500

Infection with the hepatitis B virus (HBV) may lead to an acute or chronic infection. It is generally accepted that the clinical outcome of infection depends on the balance between host immunity and viral survival strategies. In order to persist, the virus needs to have a high rate of replication and some immune-escape capabilities. Hence, HBVs lacking these properties are likely to be eliminated more rapidly by the host, leading to a lower rate of chronicity. To test this hypothesis, 177 HBV genomes from acute non-fulminant cases and 1,149 from chronic cases were retrieved from GenBank for comparative analysis. Selection of candidate nucleotides associated with the disease state was done using random guess cut-off and the Bonferroni correction. Five significant nucleotides were detected using this filtering step. Their predictive values were assessed using the support vector machine classification with five-fold cross-validation. The average prediction accuracy was 61% ± 1%, with a sensitivity of 24% ± 1%, specificity of 98% ± 1%, positive predictive value of 92% ± 4% and negative predictive value of 56% ± 1%. BCP/X, enhancer I and surface/polymerase variants were found to be associated almost exclusively with acute hepatitis. These HBV variants are novel potential markers for non-progression to chronic hepatitis.
Ocular surface disease in psoriatic patients in a developing country

Goh Y, Kwan Z, Han WH, Iqbal T, Yahya F, Khang TF, et al.

Int Ophthalmol, 2021 Jun;41(6):2139-2147.
PMID: 33788072 DOI: 10.1007/s10792-021-01771-8

PURPOSE: To evaluate ocular surface changes among patients with psoriasis in Malaysia, a developing country in Southeast Asia.
METHODS: An interdisciplinary case-control study (60 psoriasis patients and 40 control subjects) to look at the differences in ocular surface manifestations between patients with psoriasis and a group of age-, gender- and ethnicity-matched healthy controls.
RESULTS: One hundred and twenty eyes of 60 patients with psoriasis and 80 eyes of 40 healthy controls without psoriasis were included in the study. Mild-to-moderate psoriasis was found in 42 patients (70%), while 18 patients (30%) had severe psoriasis. Psoriatic arthritis was found in 19 patients (32%). Of the 60 psoriatic patients, the prevalence of ocular involvement was 65% (39/60), in which 32% (19/60) had dry eyes, 27% (16/60) had lid margin abnormalities, 33% (20/60) had cataract, and one had history of anterior uveitis. Compared to controls, ocular surface of psoriatic patients showed more eyelid margin abnormalities, higher meibomian gland loss and lower tear film break-up time. The estimated odds ratio for dry eyes in the psoriasis group was 2.2 (95% CI: 0.8-6.9).
CONCLUSION: Ocular surface disorders encompassing eyelid margin abnormalities, meibomian gland loss and tear dysfunction occur at an earlier and higher rate among psoriatic patients.
Dosage-dependent reduction of macular pigment optical density in female breast cancer patients receiving tamoxifen adjuvant therapy

Lim IL, Loo AVP, Subrayan V, Khang TF, See MH, Alip A, et al.

Breast, 2018 Jun;39:117-122.
PMID: 29660599 DOI: 10.1016/j.breast.2018.04.003

It is now increasingly common for breast cancer patients to receive adjuvant tamoxifen therapy for a period of up to 10 years. As survival rate increases, managing tamoxifen ocular toxicities is important for patients' quality of life. Macular pigments in photoreceptor cells protect against free radical damage, which can cause macular degeneration. By reducing macular pigment concentration, tamoxifen may increase the risk of macular degeneration. Here, we compared macular pigment optical density (MPOD) and central macular thickness between breast cancer patients on tamoxifen adjuvant therapy (n = 70), and a control group (n = 72). Multiple regression analysis indicated that MPOD decreases with increasing tamoxifen dosage, up to a threshold of about 20 g, after which MPOD plateaus out. Mean MPOD in the treatment group (mean = 0.40) was significantly lower (p-value = 0.02) compared to the control group (mean = 0.47) for the left eye, and for the right eye (treatment mean = 0.39; control mean = 0.48; p-value = 0.009). No significant difference in mean central macular thickness was found between the treatment and the control group (p-values > 0.4). In the control group, MPOD and central macular thickness showed significant correlation (r∼0.30; p-values 
Fulltext Size-age population structure of an endangered and anthropogenically introgressed northern Adriatic population of marble trout (Salmo marmoratus Cuv.): insights for its conservation and sustainable exploitation

Polgar G, Iaia M, Sala P, Khang TF, Galafassi S, Zaupa S, et al.

PeerJ, 2023;11:e14991.
PMID: 36949764 DOI: 10.7717/peerj.14991

Salmonid species are main actors in the Italian socio-ecological landscape of inland fisheries. We present novel data on the size-age structure of one of the remnant Italian populations of the critically endangered marble trout Salmo marmoratus, which co-occurs with other stocked non-native salmonids in a large glacial river of the Lake Maggiore basin (Northern Italy-Southern Switzerland). Like other Italian native trout populations, the Toce River marble trout population is affected by anthropogenic introgression with the non-native brown trout S. trutta. Our sample includes 579 individuals, mainly collected in the Toce River main channel. We estimated the length-weight relationship, described the population size-age structure, estimated the age-specific growth trajectories, and fit an exponential mortality model. A subset of the sample was also used to measure numerical and biomass density. The estimated asymptotic maximum length is ~105 cm total length (TL). Mean length at first maturity is ~55 cm TL, and mean length at maximum yield per recruit is ~68 cm TL. Approximately 45-70% of the population are estimated to die annually, along with a fishing annual mortality of ~37%, with an exploitation ratio of ~0.5. The frequency distribution of length classes in a sample collected by angling shows that ~80% of the individuals that could be retained according to the current recreational fishing regulations likely never reproduced, and large fish disproportionally contributing to recruitment are fished and retained. We identify possible overfishing risks posed by present regulations, and propose updated harvest-slot length limits to mitigate such risks. More detailed and long-term datasets on this system are needed to more specifically inform the fishery management and monitor the effects of any change in the management strategy on the size-age structure of the marble trout population of the Toce River.
Plasma, aqueous and vitreous homocysteine levels in proliferative diabetic retinopathy

Lim CP, Loo AV, Khaw KW, Sthaneshwar P, Khang TF, Hassan M, et al.

Br J Ophthalmol, 2012 May;96(5):704-7.
PMID: 22353698 DOI: 10.1136/bjophthalmol-2011-301044

To compare homocysteine (Hcy) concentration in the blood plasma, vitreous and aqueous of eyes with proliferative diabetic retinopathy (PDR) against control, and to investigate associations between Hcy concentration in blood plasma with that of aqueous and vitreous in these two groups.
Fulltext DeSigN: connecting gene expression with therapeutics for drug repurposing and development

Lee BK, Tiong KH, Chang JK, Liew CS, Abdul Rahman ZA, Tan AC, et al.

BMC Genomics, 2017 01 25;18(Suppl 1):934.
PMID: 28198666 DOI: 10.1186/s12864-016-3260-7

BACKGROUND: The drug discovery and development pipeline is a long and arduous process that inevitably hampers rapid drug development. Therefore, strategies to improve the efficiency of drug development are urgently needed to enable effective drugs to enter the clinic. Precision medicine has demonstrated that genetic features of cancer cells can be used for predicting drug response, and emerging evidence suggest that gene-drug connections could be predicted more accurately by exploring the cumulative effects of many genes simultaneously.
RESULTS: We developed DeSigN, a web-based tool for predicting drug efficacy against cancer cell lines using gene expression patterns. The algorithm correlates phenotype-specific gene signatures derived from differentially expressed genes with pre-defined gene expression profiles associated with drug response data (IC50) from 140 drugs. DeSigN successfully predicted the right drug sensitivity outcome in four published GEO studies. Additionally, it predicted bosutinib, a Src/Abl kinase inhibitor, as a sensitive inhibitor for oral squamous cell carcinoma (OSCC) cell lines. In vitro validation of bosutinib in OSCC cell lines demonstrated that indeed, these cell lines were sensitive to bosutinib with IC50 of 0.8-1.2 μM. As further confirmation, we demonstrated experimentally that bosutinib has anti-proliferative activity in OSCC cell lines, demonstrating that DeSigN was able to robustly predict drug that could be beneficial for tumour control.
CONCLUSIONS: DeSigN is a robust method that is useful for the identification of candidate drugs using an input gene signature obtained from gene expression analysis. This user-friendly platform could be used to identify drugs with unanticipated efficacy against cancer cell lines of interest, and therefore could be used for the repurposing of drugs, thus improving the efficiency of drug development.

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