Muhammad Muneeb

Muhammad Muneeb, David B. Ascher

Missense variant interpretation remains challenging because pathogenicity depends on heterogeneous evidence from population frequency, evolutionary conservation, transcript context, amino acid substitution severity, prior pathogenicity predictors and protein-language-model-derived features. We present AnnotateMissense, a scalable annotation, benchmarking and genome-wide prediction framework for missense variant interpretation. AnnotateMissense integrates hg38 missense variants derived from dbNSFP v5.1 with ANNOVAR annotations, dbNSFP transcript/protein descriptors, AlphaMissense scores, ESM-derived features, conservation metrics, population-frequency variables, established pathogenicity predictors and engineered amino acid/codon-context features. Using 132,714 ClinVar-labelled missense variants, we benchmarked machine-learning and deep-learning models under controlled feature configurations. The full 303-feature benchmark set achieved the strongest performance with XGBoost, reaching mean MCC = 0.9411 and ROC-AUC = 0.9950 across stratified five-fold cross-validation. Restricted naive and location-oriented feature sets achieved lower best MCC values of 0.4989 and 0.5113, respectively. Circularity-controlled ablations showed that removing prior-predictor, population-frequency and clinically overlapping evidence reduced performance, whereas excluding AlphaMissense and ESM-derived features alone had minimal effect. Temporal ClinVar validation on newly observed pathogenic/benign variants achieved MCC = 0.7613, accuracy = 0.8798 and F1-score = 0.8750. The final model was applied to 90,643,830 hg38 missense variants to generate AnnotateMissense pathogenicity scores and binary prediction labels. Code and outputs are available at https://github.com/MuhammadMuneeb007/CAGI7_Annotate_All_Missense and https://doi.org/10.5281/zenodo.19981867.

Muhammad Muneeb, David B. Ascher

Large language models (LLMs) often lack specialized knowledge for complex bioinformatics applications. We present a reproducible pipeline for fine-tuning LLMs on specialized bioinformatics data, demonstrated through two use cases: PRSGPT, focused on polygenic risk score (PRS) tools, and BioStarsGPT, trained on community forum discussions. The nine-step pipeline integrates diverse data sources, structured preprocessing, prompt-based question-answer (QA) generation (via Google Gemini), natural language inference (NLI) for quality control, semantic deduplication, clustering-based data splitting, and parameter-efficient fine-tuning using LoRA. We fine-tuned three LLMs (LLaMA-3.2-3B, Qwen2.5-7B, Gemma) and benchmarked them on over 14 lexical and semantic metrics. Qwen2.5-7B emerged as the best performer, with BLEU-4 and ROUGE-1 improvements of 82\% and 70\% for PRSGPT and 6\% and 18\% for BioStarsGPT, respectively. The open-source datasets produced include over 28,000 QA pairs for PRSGPT and 154,282 for BioStarsGPT. Human evaluation of PRSGPT yielded 61.9\% accuracy on the PRS tools comparison task, comparable to Google Gemini (61.4\%), but with richer methodological detail and accurate citations. BioStarsGPT demonstrated 59\% conceptual accuracy across 142 curated bioinformatics questions. Our pipeline enables scalable, domain-specific fine-tuning of LLMs. It enables privacy-preserving, locally deployable bioinformatics assistants, explores their practical applications, and addresses the challenges, limitations, and mitigation strategies associated with their development and use.

Muhammad Muneeb, Samuel F. Feng, Andreas Henschel

This article proposes and documents a machine-learning framework and tutorial for classifying images using mobile phones. Compared to computers, the performance of deep learning model performance degrades when deployed on a mobile phone and requires a systematic approach to find a model that performs optimally on both computers and mobile phones. By following the proposed pipeline, which consists of various computational tools, simple procedural recipes, and technical considerations, one can bring the power of deep learning medical image classification to mobile devices, potentially unlocking new domains of applications. The pipeline is demonstrated on four different publicly available datasets: COVID X-rays, COVID CT scans, leaves, and colorectal cancer. We used two application development frameworks: TensorFlow Lite (real-time testing) and Flutter (digital image testing) to test the proposed pipeline. We found that transferring deep learning models to a mobile phone is limited by hardware and classification accuracy drops. To address this issue, we proposed this pipeline to find an optimized model for mobile phones. Finally, we discuss additional applications and computational concerns related to deploying deep-learning models on phones, including real-time analysis and image preprocessing. We believe the associated documentation and code can help physicians and medical experts develop medical image classification applications for distribution.

Muhammad Muneeb, David B. Ascher

Predicting complex human traits from genetic data is challenging because different genetic, clinical, and molecular data sources often contain different parts of the signal. Here, we present EFGPP, a reproducible framework for generating, ranking, and combining multiple types of data for genotype-to-phenotype prediction. We applied EFGPP to migraine prediction using UK Biobank data from 733 individuals. The framework combined genotype-derived features, principal components, clinical and metabolomic covariates, and polygenic risk scores generated from migraine and depression GWAS using PLINK, PRSice-2, AnnoPred, and LDAK-GWAS. The best single data type achieved a test AUC of 0.644, while combining multiple data types improved performance to 0.688 using migraine-focused inputs and 0.663 using cross-trait depression-derived inputs. Genetic features alone did not outperform the covariates-only baseline, but genotype-derived features performed better than PRS alone, and depression-derived PRS showed useful predictive signal. Overall, EFGPP provides a practical proof-of-concept framework for prioritising and integrating heterogeneous genetic data sources for complex phenotype prediction.

Muhammad Muneeb, David B. Ascher

Human genetics offers a promising route to therapeutic discovery, yet practical frameworks translating genotype-derived signal into ranked target and drug hypotheses remain limited, particularly when matched disease transcriptomics are unavailable. Here we present G2DR, a genotype-first prioritization framework propagating inherited variation through genetically predicted expression, multi-method gene-level testing, pathway enrichment, network context, druggability, and multi-source drug--target evidence integration. In a migraine case study with 733 UK Biobank participants under stratified five-fold cross-validation, we imputed expression across seven transcriptome-weight resources and ranked genes using a reproducibility-aware discovery score from training and validation data, followed by a balanced integrated score for target selection. Discovery-based prioritization generalized to held-out data, achieving gene-level ROC-AUC of 0.775 and PR-AUC of 0.475, while retaining enrichment for curated migraine biology. Mapping prioritized genes to compounds via Open Targets, DGIdb, and ChEMBL yielded drug sets enriched for migraine-linked compounds relative to a global background, though recovery favoured broader mechanism-linked and off-label space over migraine-specific approved therapies. Directionality filtering separated broadly recovered compounds from mechanistically compatible candidates. G2DR is a modular framework for genetics-informed hypothesis generation, not a clinically actionable recommendation system. All outputs require independent experimental, pharmacological, and clinical validation.