bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2025.04.28.651146

Classification of outcomes in antimalarial therapeutic efficacy studies with Aster

Gerlovina, I.·Berube, S.·Briggs, J.·Murie, K.·Murphy, M.·Wesolowski, A.·Greenhouse, B.
View original source ↗Export metadata ↓

Abstract

Reliable assessment of antimalarial drug efficacy is crucial for effective response to emerging drug resistance, and therapeutic efficacy studies (TES) are the primary means of estimating in vivo efficacy. Accuracy of such estimates rests on correctly classifying recurrent infections developed during follow-up as recrudescences or new infections. Genotyping is used to guide classification, but polyclonal infections and alleles matching by chance make classification challenging, especially in high transmission settings. Match-counting algorithms currently recommended by World Health Organization are unreliable and produce biased results, necessitating development of principled statistical approaches. Modern genotyping methods such as multiplexed amplicon sequencing hold great potential for resolving recurrences and motivate the need for corresponding statistical methods able to utilize the rich data they provide. We propose an Adaptive Statistical framework for Therapeutic Efficacy and Recrudescence (Aster) that delivers accurate and consistent results by explicitly incorporating complexity of infection (COI), population allele frequencies, and imperfect detection of alleles in minority strains. Using an identity by descent approach, Aster accounts for alleles matching by chance and for a background infection relatedness structure that can otherwise lead to misclassification. The flexible framework can also use external information, such as parasite density and performance characteristics of a genotyping panel. Using simulations, we show that Aster dramatically outperforms match-counting algorithms in a wide variety of transmission settings and demonstrates consistently balanced performance that improves with more informative genotyping panels. Aster is implemented in a fast, fully scalable, and user-friendly R software package asterTES and provides accurate estimates of treatment failure for TES with any type of genotyping data, facilitating reliable evaluation of drug efficacy and effective management of malaria.

Source connections

Explore related subjects

geneticsPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Gerlovina, I., Berube, S., Briggs, J., Murie, K., Murphy, M., Wesolowski, A., Greenhouse, B.. 2025-05-01. Classification of outcomes in antimalarial therapeutic efficacy studies with Aster. https://doi.org/10.1101/2025.04.28.651146

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

OPA1 controls mitochondrial dysfunction-driven liver fibrosis in MASLD

Progressive hepatic fibrosis is the principal determinant of morbidity and mortality in metabolic dysfunction-associated steatotic liver disease and steatohepatitis (MASLD/MASH). Mitochondrial dysfunction is a hallmark of MASH, and the release of mitochondrial damage-associated molecular patterns (mito-DAMPs) from injured hepatocytes can promote fibrosis. However, how mitochondrial dynamics and quality control shape the fibrotic response in MASLD/MASH remains unclear. Here, through large-scale genomic analyses of mitochondrial genes governing mitophagy, fusion and fission in human MASLD, with a power-equivalent sample size of approximately 700,000 individuals, we identify a strong association between hepatic fibrosis and the mitochondrial fusion factor dynamin-like GTPase optic atrophy 1 (OPA1). OPA1 transcripts and protein abundance in the liver epithelium were progressively dysregulated with advancing fibrosis. In mice, hepatocyte-specific OPA1 loss alone was sufficient to induce hepatic stellate cell activation and fibrosis in zone 3, promoted the release of mito-DAMPs into the circulation and exacerbated fibrosis in experimental MASH. These findings identify OPA1 as a central regulator of the hepatic fibrotic response and connect defective mitochondrial homeostasis to mito-DAMP release, hepatic stellate cell activation and fibrosis in MASLD.

genetics↗
bioRxiv2026

Temporal control of mitochondrial mutagenesis reveals the fate of mtDNA mutations with age

Mutations in the mitochondrial genome (mtDNA) play a critical role in the aging process and a wide variety of age-related diseases. However, it remains unclear when the mutations that drive physiological decline arise. To answer this question, we generated a new mouse model in which mitochondrial mutagenesis can be confined to a defined window of time. Surprisingly, we found that mutations that arise during the first two months of life are sufficient to drive a wide variety of age-related pathologies, and that the severity of this pathology is broadly regulated by distinct, tissue-specific selective pressures that control the fate of mtDNA mutations with age. Further, we found that selection against deleterious variants can be modulated by manipulation of mitochondrial fusion in vitro and in vivo. These observations raise the possibility that in some tissues, the pace of aging is pre-determined by events that occur early in life and that interventions targeting mitochondrial fusion may be able to slow down or reverse the expansion of these pathogenic variants. These results carry far-reaching implications for strategies aimed at preventing or delaying age-related decline.

genetics↗
bioRxiv2026

Innate immune stress pathway activation underlies heterochromatin dysfunction pathology

Heterochromatin loss disrupts nuclear architecture, gene regulation and repetitive element silencing, and is associated with diverse human diseases. However, mechanisms linking heterochromatin dysfunction to pathological phenotypes remain unclear. Using genetic interaction screening and genomic analyses in C. elegans, we identify secondary activation of the Intracellular Pathogen Response (IPR), an innate immune stress pathway, as a major contributor to heterochromatin mutant phenotypes. Constitutive IPR activation phenocopies slow growth and indirect transcriptional changes observed in these mutants. Depletion of genetic enhancers further increased, whereas suppressor RNAi attenuated IPR activation, with direct heterochromatin targets remaining substantially deregulated. Notably, many suppressors encode active chromatin components, and mild reduction of RNA polymerase II activity ameliorates growth defects in C. elegans HP1 mutants and human HP1-deficient cells. Our findings reveal secondary stress response activation as an important mechanism linking heterochromatin dysfunction to pathology and identify transcriptional dampening as a potential therapeutic strategy for mitigating these effects.

genetics↗