Biology subjects

Carter, H.

Publications and source records attributed to Carter, H..

At least 37 records · Page 2Linked to original sources

bioRxiv2022

EUGENe: A Python toolkit for predictive analyses of regulatory sequences

Deep learning (DL) has become a popular tool to study cis-regulatory element function. Yet efforts to design software for DL analyses in genomics that are Findable, Accessible, Interoperable and Reusable (FAIR) have fallen short of fully meeting these criteria. Here we present EUGENe (Elucidating the Utility of Genomic Elements with Neural Nets), a FAIR toolkit for the analysis of labeled sets of nucleotide sequences with DL. EUGENe consists of a set of modules that empower users to execute the key functionality of a DL workflow: 1) extracting, transforming and loading sequence data from many common file formats, 2) instantiating, initializing and training diverse model architectures, and 3) evaluating and interpreting model behavior. We designed EUGENe to be simple; users can develop workflows on new or existing datasets with two customizable Python objects, annotated sequence data (SeqData) and PyTorch models (BaseModel). The modularity and simplicity of EUGENe also make it highly extensible and we illustrate these principles through application of the toolkit to three predictive modeling tasks. First, we train and compare a set of built-in models along with a custom architecture for the accurate prediction of activities of plant promoters from STARR-seq data. Next, we apply EUGENe to an RNA binding prediction task and showcase how seminal model architectures can be retrained in EUGENe or imported from Kipoi. Finally, we train models to classify transcription factor binding by wrapping functionality from Janngu, which can efficiently extract sequences in BED file format from the human genome. We emphasize that the code used in each use case is simple, readable, and well documented (https://eugene-tools.readthedocs.io/en/latest/index.html). We believe that EUGENe represents a springboard toward a collaborative ecosystem for DL applications in genomics research. EUGENe is available for download on GitHub (https://github.com/cartercompbio/EUGENe) along with several introductory tutorials and for installation on PyPi (https://pypi.org/project/eugene-tools/).

bioinformatics↗

bioRxiv2022

Antibody optimization enabled by artificial intelligence predictions of binding affinity and naturalness

Traditional antibody optimization approaches involve screening a small subset of the available sequence space, often resulting in drug candidates with suboptimal binding affinity, developability or immunogenicity. Based on two distinct antibodies, we demonstrate that deep contextual language models trained on high-throughput affinity data can quantitatively predict binding of unseen antibody sequence variants. These variants span a KD range of three orders of magnitude over a large mutational space. Our models reveal strong epistatic effects, which highlight the need for intelligent screening approaches. In addition, we introduce the modeling of "naturalness", a metric that scores antibody variants for similarity to natural immunoglobulins. We show that naturalness is associated with measures of drug developability and immunogenicity, and that it can be optimized alongside binding affinity using a genetic algorithm. This approach promises to accelerate and improve antibody engineering, and may increase the success rate in developing novel antibody and related drug candidates.

bioinformatics↗

bioRxiv2022

Rab11-FIP1C is dispensable for HIV-1 replication in primary CD4+ T cells but its role is cell-type-dependent in immortalized human T-cell lines

The HIV-1 envelope glycoprotein (Env) contains a long cytoplasmic tail harboring highly conserved motifs that direct Env trafficking and incorporation into virions and promote efficient virus spread. The cellular trafficking factor Rab11a family interacting protein 1C (FIP1C) has been implicated in the directed trafficking of Env to sites of viral assembly. In this study, we confirm that siRNA-mediated depletion of FIP1C in HeLa cells modestly reduces Env incorporation into virions. To determine whether FIP1C is required for Env incorporation and HIV-1 replication in physiologically relevant cells, CRISPR/Cas9 technology was used to knock out the expression of this protein in several human T-cell lines - Jurkat E6.1, SupT1 and H9 - and in primary human CD4+ T cells. FIP1C knock-out caused modest reductions in Env incorporation in SupT1 cells but did not inhibit virus replication in SupT1 or Jurkat E6.1 T-cell lines. In H9 cells, FIP1C knock-out caused a cell-density-dependent defect in virus replication. In primary CD4+ T cells, FIP1C knock-out had no effect on HIV-1 replication. Furthermore, HTLV-I transformed cell lines that are permissive for HIV-1 replication do not express FIP1C. Mutation of an aromatic motif in the Env cytoplasmic tail - Y795W - implicated in FIP1C-mediated Env incorporation impaired virus replication independently of FIP1C expression in SupT1, Jurkat E6.1, H9, and primary T cells. Together, these results indicate that while FIP1C may contribute to HIV-1 Env incorporation in some contexts, additional and potentially redundant host factors are likely required for Env incorporation and virus dissemination in T cells. ImportanceThe incorporation of the HIV-1 envelope (Env) glycoproteins, gp120 and gp41, into virus particles is critical for virus infectivity. Gp41 contains a long cytoplasmic tail that has been proposed to interact with host cell factors, including the trafficking factor Rab11a family interacting protein 1C (FIP1C). To investigate the role of FIP1C in relevant cell types - human T-cell lines and primary CD4+ T cells - we used CRISPR/Cas9 to knock out FIP1C expression and examined the effect on HIV-1 Env incorporation and virus replication. We observed that in two of the T-cell lines examined (Jurkat E6.1 and SupT1) and in primary CD4+ T cells, FIP1C knockout did not disrupt HIV-1 replication, whereas FIP1C knockout reduced Env expression and delayed replication in H9 cells. The results indicate that while FIP1C may contribute to Env incorporation in some cell lines, it is not an essential factor for efficient HIV-1 replication in primary CD4+ T cells.

microbiology↗

bioRxiv2022

Mitonuclear interactions produce extreme differences in response to redox stress

Incompatibilities between mitochondrial and nuclear genes can perturb respiration, biosynthesis, signalling and gene expression. Here we investigate whether mild mitonuclear incompatibilities alter response to redox stress induced by N-acetyl cysteine (NAC). We studied three Drosophila melanogaster lines with mitochondrial genomes either coevolved (WT) or mildly mismatched (BAR, COX) to an isogenic nuclear background. Responses to NAC varied substantially with mitonuclear genotype, sex, tissue and dose. NAC caused infertility and high mortality in some groups but not others. Using tissue-specific fluorespirometry, we show that NAC did not alter H2O2 flux but suppressed complex I-linked respiration in female flies, maintaining a reduced glutathione pool. High mortality in BAR females was associated with severe suppression of complex I-linked respiration, rising H2O2 flux in ovaries and oxidation of the glutathione pool. Our results suggest that redox stress is attenuated by suppression of complex-I linked respiration, to the point of death in some mitonuclear lines.

biochemistry↗

bioRxiv2021

The landscape of extrachromosomal circular DNA in medulloblastoma

Extrachromosomal circular DNA (ecDNA) is an important driver of aggressive tumor growth, promoting high oncogene copy number, intratumoral heterogeneity, accelerated evolution of drug resistance, enhancer rewiring, and poor outcome. ecDNA has been reported in medulloblastoma (MB), the most common malignant pediatric brain tumor, but the ecDNA landscape and its association with specific MB subgroups, its impact on enhancer rewiring, and its potential clinical implications, are not known. We assembled a retrospective cohort of 468 MB patient samples with available whole genome sequencing (WGS) data covering the four major MB subgroups WNT, SHH, Group 3 and Group 4. Using computational methods for the detection and reconstruction of ecDNA1, we find ecDNA in 82 patients (18%) and observe that ecDNA+ MB patients are more than twice as likely to relapse and three times as likely to die of disease. In addition, we find that individual medulloblastoma tumors often harbor multiple ecDNAs, each containing different amplified oncogenes along with co-amplified non-coding regulatory enhancers. ecDNA was substantially more prevalent among 31 analyzed patient-derived xenograft (PDX) models and cell lines than in our patient cohort. By mapping the accessible chromatin and 3D conformation landscapes of MB tumors that harbor ecDNA, we observe frequent candidate "enhancer rewiring" events that spatially link oncogenes with co-amplified enhancers. Our study reveals the frequency and diversity of ecDNA in a subset of highly aggressive tumors and suggests enhancer rewiring as a frequent oncogenic mechanism of ecDNAs in MB. Further, these results demonstrate that ecDNA is a frequent and potent driver of poor outcome in MB patients.

cancer biology↗

bioRxiv2021

Immunogenic potential of neopeptides depends on parent protein subcellular location

Antigen presentation via the major histocompatibility complex (MHC) is essential for anti-tumor immunity, however the rules that determine what tumor-derived peptides will be immunogenic are still incompletely understood. Here we investigate whether protein subcellular location driven constraints on accessibility of peptides to the MHC associate with potential for peptide immunogenicity. Analyzing over 380,000 peptides from studies of MHC presentation and peptide immunogenicity, we find clear spatial biases in both eluted and immunogenic peptides. We find that including parent protein location improves prediction of peptide immunogenicity in multiple datasets. In human immunotherapy cohorts, location was associated with response to a neoantigen vaccine, and immune checkpoint blockade responders generally had a higher burden of neopeptides from accessible locations. We conclude that protein subcellular location adds important information for optimizing immunotherapies. HighlightsO_LIPeptides eluted from class I and II MHC reflect biases in the subcellular location of the parent proteins C_LIO_LIAn embedding-based indicator of parent protein location improves prediction of neoepitope immunogenicity and immunotherapy response C_LIO_LINeoepitope location improves estimation of effective neoantigen burden and stratification of potential for immunotherapy response C_LI

bioinformatics↗

bioRxiv2021

Autoimmune Alleles at the Major Histocompatibility Locus Modify Melanoma Susceptibility

Autoimmunity and cancer represent two different aspects of immune dysfunction. Autoimmunity is characterized by breakdowns in immune self-tolerance, while impaired immune surveillance can allow for tumorigenesis. The class I major histocompatibility complex (MHC-I), which displays derivatives of the cellular peptidome for immune surveillance by CD8+ T cells, serves as a common genetic link between these conditions. As melanoma-specific CD8+ T-cells have been shown to target melanocyte-specific peptide antigens more often than melanoma-specific antigens, we investigated whether vitiligo and psoriasis predisposing MHC-I alleles conferred a melanoma protective effect. In individuals with cutaneous melanoma from both The Cancer Genome Atlas (N = 451) and an independent validation cohort (N = 586), MHC-I autoimmune allele carrier status was significantly associated with a later age of melanoma diagnosis. Furthermore, MHC-I autoimmune allele carriers were significantly associated with decreased risk of developing melanoma in the Million Veterans Program cohort (OR = 0.962, p = 0.024). Existing melanoma polygenic risk scores (PRS) did not predict autoimmune allele carrier status, suggesting these alleles provide new risk-relevant information. Mechanisms of autoimmune protection were neither associated with improved melanoma-driver mutation association nor improved gene-level conserved antigen presentation relative to common alleles (population frequency > 1%). However, autoimmune alleles showed higher affinity relative to common alleles for particular windows of melanocyte conserved antigens suggesting a potential relationship between antigen processing, binding, and cell-surface presentation. Overall, this study presents evidence that MHC-I autoimmune risk alleles modulate melanoma risk unaccounted for by current PRS.

cancer biology↗

bioRxiv2021

Effect of Substrate Stiffness on Human Intestinal Enteroids Infectivity by Enteroaggregative Escherichia coli

Human intestinal enteroids (HIE) models have contributed significantly to our understanding of diarrheal diseases and other intestinal infections, but their routine culture conditions fail to mimic the mechanical environment of the native intestinal wall. Because the mechanical characteristics of the intestine significantly alter how pathogens interact with the intestinal epithelium, we used different concentrations of polyethylene glycol (PEG) to generate soft ([~]2 kPa), medium ([~]10 kPa), and stiff ([~]100 kPa) hydrogel biomaterial scaffolds. The height of HIEs cultured in monolayers atop these hydrogels was 18 {micro}m whereas HIEs grown on rigid tissue culture surfaces (with stiffness in the GPa range) were 10 {micro}m. Substrate stiffness also influenced the amount of enteroaggregative E. coli (EAEC strain 042) adhered to the HIEs. We quantified a striking difference in adherence pattern; on the medium and soft gels, the bacteria formed clusters of >100 and even >1000 on both duodenal and jejunal HIEs (such as would be found in biofilms), but did not on glass slides and stiff hydrogels. All hydrogel cultured HIEs showed significant enrichment for gene and signaling pathways related to epithelial differentiation, cell junctions and adhesions, extracellular matrix, mucins, and cell signaling compared to the HIEs cultured on rigid tissue culture surfaces. Collectively, these results indicate that the HIE monolayers cultured on the hydrogels are primed for a robust engagement with their mechanical environment, and that the soft hydrogels promote the formation of larger EAEC aggregates, likely through an indirect differential effect on mucus. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=98 SRC="FIGDIR/small/448533v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@f9c7b3org.highwire.dtl.DTLVardef@a5d5feorg.highwire.dtl.DTLVardef@184224forg.highwire.dtl.DTLVardef@1e8a28d_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

bioengineering↗

bioRxiv2021

Germline variants that influence the tumor immune microenvironment also drive response to immunotherapy

With the continued promise of immunotherapy as an avenue for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Approaches that intersect SNP modifiers of molecular phenotype, such as gene expression, with disease phenotypes have shown promise for implicating causal genetic factors. Here we evaluated 194 literature-curated TIME associations and 890 associations detected with 157 immune phenotype (IP) components found using genotypes from over 8,000 individuals in The Cancer Genome Atlas. Of these 1084, 233 associations comprising 219 unique TIME-SNPs were also cancer relevant, associating with cancer risk, survival, and/or immunotherapy treatment response. Many cancer relevant TIME-SNPS overlapped regions of active transcription, and were associated with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. TIME-SNPs associated with cancer risk and response to immunotherapy implicated genes involved in antigen presentation, especially by antigen presenting cells. The strongest associations with survival were with PD-L1 and CTLA-4, suggesting that SNPs modifying the potential for immune evasion could contribute to disease progression. To assess whether our approach could reveal novel cancer immunotherapy targets, we inhibited CTSS, a gene implicated by cancer risk and immunotherapy response-associated TIME-SNPs; CTSS inhibition resulted in slowed tumor growth and extended survival in vivo. These results validate the potential of cancer relevant TIME-SNPs to implicate target genes for countering immune suppressive characteristics of the TIME and set the stage for future host genetics analysis integrating germline variation and TIME characteristics. SignificanceA systematic screen for common germline variants associated with the tumor immune microenvironment across > 8000 tumors reveals novel cancer risk factors and targets for immunotherapy.

cancer biology↗

bioRxiv2021

Predicting functional consequences of mutations using molecular interaction network features

Variant interpretation remains a central challenge for precision medicine. Missense variants are particularly difficult to understand as they change only a single amino acid in protein sequence yet can have large and varied effects on protein activity. Numerous tools have been developed to identify missense variants with putative disease consequences from protein sequence and structure. However, biological function arises through higher order interactions among proteins and molecules within cells. We therefore sought to capture information about the potential of missense mutations to perturb protein interaction networks by integrating protein structure and interaction data. We developed 16 network-based annotations for missense mutations that provide orthogonal information to features classically used to prioritize variants. We then evaluated them in the context of a proven machine-learning framework for variant effect prediction across multiple benchmark datasets to demonstrate their potential to improve variant classification. Interestingly, network features resulted in larger performance gains for classifying somatic mutations than for germline variants, possibly due to different constraints on what mutations are tolerated at the cellular versus organismal level. Our results suggest that modeling variant potential to perturb context-specific interactome networks is a fruitful strategy to advance in silico variant effect prediction.

bioinformatics↗

bioRxiv2021

Potential global impact of the N501Y mutation on MHC-II presentation and immune escape

The B.1.1.7 SARS-CoV-2 variant, characterized by the N501Y mutation, is rapidly emerging, raising concerns about its effectiveness on natural as well as vaccine-induced adaptive viral immunity at the population level. Since CD4 T cell responses are of critical importance to the antibody response, we examined the global effects of N501Y mutation on MHC-II presentation compared to the N501 wildtype and found poorer presentation across the majority of MHC-II alleles. This suggests that the N501Y mutation may not only diminish binding of antibodies to the RBD but also interfere with their production by weakening the cooperation between T and B cells, facilitating immune escape.

bioinformatics↗

bioRxiv2020

MHC-II constrains the natural neutralizing antibody response to the SARS-CoV-2 spike RBM in humans

SARS-CoV-2 antibodies develop within two weeks of infection, but wane relatively rapidly post-infection, raising concerns about whether antibody responses will provide protection upon re-exposure. Here we revisit T-B cooperation as a prerequisite for effective and durable neutralizing antibody responses centered on a mutationally constrained RBM B cell epitope. T-B cooperation requires co-processing of B and T cell epitopes by the same B cell and is subject to MHC-II restriction. We evaluated MHC-II constraints relevant to the neutralizing antibody response to a mutationally-constrained B cell epitope in the receptor binding motif (RBM) of the spike protein. Examining common MHC-II alleles, we found that peptides surrounding this key B cell epitope are predicted to bind poorly, suggesting a lack MHC-II support in T-B cooperation, impacting generation of high-potency neutralizing antibodies in the general population. Additionally, we found that multiple microbial peptides had potential for RBM cross-reactivity, supporting previous exposures as a possible source of T cell memory. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC="FIGDIR/small/424449v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@d332ccorg.highwire.dtl.DTLVardef@1ac1a95org.highwire.dtl.DTLVardef@5688dorg.highwire.dtl.DTLVardef@1133d83_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2020

The unfolded protein response links tumor aneuploidy to local immune dysregulation

Aneuploidy is a chromosomal abnormality associated with poor prognosis in many cancer types. Here we tested the hypothesis that the unfolded protein response (UPR) links mechanistically aneuploidy and local immune dysregulation. Using a single somatic copy-number alteration (SCNA) score inclusive of whole-chromosome, arm and focal chromosome alterations in a pan-cancer analysis of 9,375 samples in The Cancer Genome Atlas (TCGA) database, we found an inverse correlation with a cytotoxicity (CYT) score across disease stages. Co-expression patterns of UPR genes changed substantially between SCNAlow and SCNAhigh groups. Pathway activity scores showed increased activity by multiple branches of the UPR in response to aneuploidy. The PERK branch showed the strongest association with a reduced CYT score. The conditioned medium of aneuploid cells transmitted XBP1 splicing and caused IL-6 and Arginase1 transcription in receiver bone marrow-derived macrophages. We propose the UPR as a mechanistic link between aneuploidy and immune dysregulation in the tumor microenvironment. Statement of SignificanceAneuploidy accumulates over the life of a tumor and is associated with poor prognosis. Tumor progression is also associated with a progressive immune dysregulation. To explain these complex and concurrent disorders we tested the hypothesis that the unfolded protein could represent the link between aneuploidy and a dysregulation of local immunity favoring tumor progression.

cancer biology↗

bioRxiv2020

Discovering biomarkers of chemotherapy resistance using in vitro evolution in haploid human cells

BackgroundIn vitro evolution and whole genome analysis has proven to be a powerful method for studying the mechanism of action of small molecules in many haploid microbes but has generally not been applied to human cell lines in part because their diploid state complicates the identification of variants that confer drug resistance. To determine if haploid human cell could be used in MOA studies, we evolved resistance to five different anticancer drugs (doxorubicin, gemcitabine, etoposide, topotecan, and paclitaxel) using a near-haploid cell line (HAP1) and then analyzed the genomes of the drug resistant clones, developing a bioinformatic pipeline that involved filtering for high frequency alleles predicted to change protein sequence, or alleles which appeared in the same gene for multiple independent selections with the same compound. Applying the filter to sequences from 28 drug resistant clones identified a set of 21 genes which was strongly enriched for known resistance genes or known drug targets (TOP1, TOP2A, DCK, WDR33, SLCO3A1). In addition, some lines carried structural variants that encompassed additional known resistance genes (ABCB1, WWOX and RRM1). Gene expression knockdown and knockout experiments of 10 validation targets showed a high degree of specificity and accuracy in our calls and demonstrates that the same drug resistance mechanisms found in diverse clinical samples can be evolved, discovered and studied in an isogenic background.

cancer biology↗

bioRxiv2020

IRE1? regulates macrophage polarization, PD-L1 expression and tumor survival

In the tumor microenvironment local immune dysregulation is driven in part by macrophages and dendritic cells that are polarized to a mixed proinflammatory/immune suppressive phenotype. The unfolded protein response (UPR) is emerging as the possible origin of these events. Here we report that the inositol-requiring enzyme 1 (IRE1) branch of the UPR is directly involved in the polarization of macrophages in vitro and in vivo, including the upregulation of IL-6, IL-23, Arginase1, as well as surface expression of CD86 and PD-L1. Macrophages in which the IRE1/Xbp1 axis is blocked pharmacologically or deleted genetically have significantly reduced polarization, and CD86 and PD-L1 expression, which was induced independent of IFN{gamma} signaling suggesting a novel mechanism in PD-L1 regulation in macrophages. Mice with IRE1- but not Xbp1-deficient macrophages showed greater survival than controls when implanted with B16.F10 melanoma cells. Remarkably, we found a significant association between the IRE1 gene signature and CD274 gene expression in tumor-infiltrating macrophages in humans. RNASeq analysis showed that bone marrow derived macrophages with IRE1 deletion lose the integrity of the gene connectivity characteristic of regulated IRE1-dependent decay (RIDD) and the ability to activate CD274 gene expression. Thus, the IRE1/Xbp1 axis drives the polarization of macrophages in the tumor microenvironment initiating a complex immune dysregulation leading to failure of local immune surveillance.

cancer biology↗

bioRxiv2019

Germline and somatic genetic variants in the p53 pathway interact to affect cancer risk, progression and drug response

Insights into oncogenesis derived from cancer susceptibility loci could facilitate better cancer management and treatment through precision oncology. However, therapeutic applications have thus far been limited by our current lack of understanding regarding both their interactions with somatic cancer driver mutations and their influence on tumorigenesis. Here, by integrating germline datasets relating to cancer susceptibility with tumour data capturing somatically-acquired genetic variation, we provide evidence that single nucleotide polymorphism (SNPs) and somatic mutations in the p53 tumor suppressor pathway can interact to influence cancer development, progression and treatment response. We go on to provide human genetic evidence of a tumor-promoting role for the pro-survival activities of p53, which supports the development of more effective therapy combinations through their inhibition in cancers retaining wild-type p53. SignificanceWe describe significant interactions between heritable and somatic genetic variants in the p53 pathway that affect cancer susceptibility, progression and treatment response. Our results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and identify novel therapeutic targets.

cancer biology↗

bioRxiv2019

GPCRs show widespread differential mRNA expression and frequent mutation and copy number variation in solid tumors

G protein-coupled receptors (GPCRs) are the most widely targeted gene family for FDA-approved drugs. To assess possible roles for GPCRs in cancer, we analyzed Cancer Genome Atlas data for mRNA expression, mutations, and copy number variation (CNV) in 20 categories/45 sub-types of solid tumors and quantified differential expression of GPCRs by comparing tumors against normal tissue from the GTEx database. GPCRs are over-represented among coding genes with elevated expression in solid tumors; most tumor types differentially express >50 GPCRs, including many targets for approved drugs, hitherto largely unrecognized as targets of interest in cancer. GPCR mRNA signatures characterize specific tumor types, indicate survival and correlate with expression of cancer-related pathways. Tumor GPCR mRNA signatures have prognostic relevance for survival and correlate with expression of numerous cancer-related genes and pathways. GPCR expression in tumors is largely independent of staging/grading/metastasis/driver mutations and GPCRs expressed in cancer cell lines parallels that measured in tumors. Certain GPCRs are frequently mutated and appear to be hotspots, serving as bellwethers of accumulated genomic damage. CNV of GPCRs while common, does not generally correlate with mRNA expression. We suggest a previously under-appreciated role for GPCRs in cancer, perhaps as functional oncogenes, biomarkers, surface antigens and pharmacological targets.

bioinformatics↗

bioRxiv2019

The effectiveness and cost effectiveness of a hospital avoidance program in a residential aged care facility

BackgroundResidential aged care facility residents experience high rates of hospital admissions which are stressful, costly and often preventable.\n\nDesignProspective pre-post cohort study and decision model analysis\n\nInterventionA decision-support tool was implemented to enable nursing staff to detect, refer and quickly respond to early signals of a deteriorating resident. Advanced clinical skills training, new diagnostic equipment and guided support from clinical lead nurses and nurse practitioners was provided to support nursing staff in the delivery of appropriate sub-acute care.\n\nOutcome measuresRate of hospital admissions; length of stay; incremental cost per QALY; net monetary benefit.\n\nResultsThe hospital avoidance program was associated with a 19% reduction in annual hospital admissions and a 31% reduction in the average length of stay. When modelled in a cohort of 1,000 residents the program resulted in a total of 1,606 fewer hospital bed days per annum. This contributed to a total cost saving of $2.6 million and 0.62 incremental QALYs gained per 1,000 residents. The program had a positive net monetary benefit and was considered cost-effective, even when the willingness to pay for health care gains was set to zero. A probabilistic sensitivity analysis estimated that there was an 86% probability that the program was cost-effective after taking the uncertainty of the model inputs into account.\n\nConclusionsThis study provides compelling evidence for the effectiveness and cost-effectiveness of a RACF nurse led sub-acute care program in preventing unnecessary hospital admissions.

epidemiology↗