MOTIVATION: Single-cell technologies enable high-resolution cellular studies but face challenges in identifying differential features due to data complexity. RESULTS: We present OTMODE, a non-parametric method using unbalanced Sinkhorn algorithm and Wald test to improve differential feature identification in single-cell multi-omics data. Under simulation, OTMODE achieved superior performance (average 90% F1 score; average 92% AUC score) with high efficiency (2.2 s for 5000 cells). In practice, it shows greater sensitivity than other state-of-the-art methods in detecting meaningful processes and can evaluate annotation accuracy by identifying potentially misannotated clusters from auto-annotation tools. Furthermore, OTMODE integrates seamlessly with Scanpy, offering a user-friendly solution for researchers. AVAILABILITY AND IMPLEMENTATION: OTMODE is freely available at https://github.com/Eggong/OTMODE and also available at https://pypi.org/project/OTMODE/.

SUMMARY: With the recent advancement in single-cell RNA-sequencing technologies and the increased availability of integrative tools, challenges arise in easy and fast access to large collections of cell atlas. Existing cell atlas portals rarely are open sourced and adaptable, and do not support meta-analysis at cell level. Here, we present an open source, highly optimized and scalable architecture, named Scope+, to allow quick access, meta-analysis and cell-level selection of the atlas data. We applied this architecture to our well-curated 5 million COVID-19 blood and immune cells, as a portal called Covidscope. We achieved efficient access to atlas-scale data via three strategies, such as cell-as-unit data modelling, novel database optimization techniques and innovative software architectural design. Scope+ serves as an open source architecture for researchers to build on with their own atlas. AVAILABILITY AND IMPLEMENTATION: The COVID-19 web portal, data and meta-analysis are available on Covidscope (https://covidsc.d24h.hk/). User tutorials on how to implement Scope+ architecture with their atlases can be found at https://hiyin.github.io/scopeplus-user-tutorial/. Scope+ source code can be found at https://doi.org/10.5281/zenodo.14174632 and https://github.com/hiyin/scopeplus.