COMBImage: a modular parallel processing framework for pairwise drug combination analysis that quantifies temporal changes in label-free video microscopy movies

Abstract

BackgroundLarge-scale pairwise drug combination analysis has lately gained momentum in drug discovery and development projects, mainly due to the employment of advanced experimental-computational pipelines. This is fortunate as drug combinations are often required for successful treatment of complex diseases. Furthermore, most new drugs cannot totally replace the current standard-of-care medication, but rather have to enter clinical use as add-on treatment. However, there is a clear deficiency of computational tools for label-free and temporal image-based drug combination analysis that go beyond the conventional but relatively uninformative end point measurements.ResultsCOMBImage is a fast, modular and instrument independent computational framework for in vitro pairwise drug combination analysis that quantifies temporal changes in label-free video microscopy movies. Jointly with automated analyses of temporal changes in cell morphology and confluence, it performs and displays conventional cell viability and synergy end point analyses. The image processing algorithms are parallelized using Google’s MapReduce programming model and optimized with respect to method-specific tuning parameters. COMBImage is shown to process time-lapse microscopy movies from 384-well plates within minutes on a single quad core personal computer.This framework was employed in the context of an ongoing drug discovery and development project focused on glioblastoma multiforme; the most deadly form of brain cancer. Interesting add-on effects of two investigational cytotoxic compounds when combined with vorinostat were revealed on recently established clonal cultures of glioma-initiating cells from patient tumor samples. Therapeutic synergies, when normal astrocytes were used as a toxicity cell model, reinforced the pharmacological interest regarding their potential clinical use.ConclusionsCOMBImage enables, for the first time, fast and optimized pairwise drug combination analyses of temporal changes in label-free video microscopy movies. Providing this jointly with conventional cell viability based end point analyses, it could help accelerating and guiding any drug discovery and development project, without use of cell labeling and the need to employ a particular live cell imaging instrument.Electronic supplementary materialThe online version of this article (10.1186/s12859-018-2458-x) contains supplementary material, which is available to authorized users.

COMBImage2: a parallel computational framework for higher-order drug combination analysis that includes automated plate design, matched filter based object counting and temporal data mining

“…The intra-plate QC procedure is fully automated and incorporated in all different computational modules. The corresponding algorithm is identical to the one reported in our previous work [9]. Briefly, it checks if at early (ideally untreated) time points, all experimental wells have similar feature vectors (i.e., hierarchical histograms).…”

“…It consists of 6 different modules in total, which are briefly presented below: COMBO-Pick automatically generates 384-well randomized layouts for any type of drug combination experiments by requiring only a simple user-defined text specification file.COMBO-V offers cell viability and synergy (end point) analyses and visualization. The current version of COMBO-V is able to analyze higher-order and exhaustive drug combination experiments by extending our previously reported scaled Bliss and therapeutic synergy analyses [9]. COMBO-C offers automated quantification and visualization of temporal changes in cell growth/confluence.…”

“…Ideally such in vitro evaluations should not be restricted to the widely employed single endpoint analyses, such as cell viability, but rather provide temporal information about changes relative to untreated controls. In order to meet this need, the previously introduced computational framework, COMBImage [9], was designed for label-free time-lapse video microscopy (TLVM) based analysis of pairwise drug combination experiments. COMBImage has already been successfully used in different ongoing and completed DDD projects but, as presented in more detail below, it still has some obvious limitations.…”

“…COMBO-V offers cell viability and synergy (end point) analyses and visualization. The current version of COMBO-V is able to analyze higher-order and exhaustive drug combination experiments by extending our previously reported scaled Bliss and therapeutic synergy analyses [9].…”

“…The tailor made image processing algorithms of COMBImage2 are implemented using the MapReduce programming model [24] with the goal to offer fast and scalable analyses independently of instruments, infrastructures and applications [9]. COMBImage2 is distributed as a package of 6 standalone applications for Windows together with all raw data of the corresponding case study [25–27].…”