RESUMO
Interferon-gamma (IFNG) augments immune function yet promotes T cell exhaustion through PDL1. How these opposing effects are integrated to impact immune checkpoint blockade (ICB) is unclear. We show that while inhibiting tumor IFNG signaling decreases interferon-stimulated genes (ISGs) in cancer cells, it increases ISGs in immune cells by enhancing IFNG produced by exhausted T cells (TEX). In tumors with favorable antigenicity, these TEX mediate rejection. In tumors with neoantigen or MHC-I loss, TEX instead utilize IFNG to drive maturation of innate immune cells, including a PD1+TRAIL+ ILC1 population. By disabling an inhibitory circuit impacting PD1 and TRAIL, blocking tumor IFNG signaling promotes innate immune killing. Thus, interferon signaling in cancer cells and immune cells oppose each other to establish a regulatory relationship that limits both adaptive and innate immune killing. In melanoma and lung cancer patients, perturbation of this relationship is associated with ICB response independent of tumor mutational burden.
Assuntos
Imunidade Adaptativa/imunologia , Imunidade Inata/imunologia , Interferon gama/genética , Interferon gama/metabolismo , Neoplasias Pulmonares/imunologia , Melanoma/imunologia , Transferência Adotiva , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Linhagem Celular Tumoral , Estudos de Coortes , Feminino , Técnicas de Inativação de Genes , Humanos , Interferon gama/antagonistas & inibidores , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Melanoma/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Intervalo Livre de Progressão , RNA-Seq , TransfecçãoRESUMO
BACKGROUND: The cost-effectiveness of screening the U.S. population for Centers for Disease Control and Prevention (CDC) Tier 1 genomic conditions is unknown. OBJECTIVE: To estimate the cost-effectiveness of simultaneous genomic screening for Lynch syndrome (LS), hereditary breast and ovarian cancer syndrome (HBOC), and familial hypercholesterolemia (FH). DESIGN: Decision analytic Markov model. DATA SOURCES: Published literature. TARGET POPULATION: Separate age-based cohorts (ages 20 to 60 years at time of screening) of racially and ethnically representative U.S. adults. TIME HORIZON: Lifetime. PERSPECTIVE: U.S. health care payer. INTERVENTION: Population genomic screening using clinical sequencing with a restricted panel of high-evidence genes, cascade testing of first-degree relatives, and recommended preventive interventions for identified probands. OUTCOME MEASURES: Incident breast, ovarian, and colorectal cancer cases; incident cardiovascular events; quality-adjusted survival; and costs. RESULTS OF BASE-CASE ANALYSIS: Screening 100 000 unselected 30-year-olds resulted in 101 (95% uncertainty interval [UI], 77 to 127) fewer overall cancer cases and 15 (95% UI, 4 to 28) fewer cardiovascular events and an increase of 495 quality-adjusted life-years (QALYs) (95% UI, 401 to 757) at an incremental cost of $33.9 million (95% UI, $27.0 million to $41.1 million). The incremental cost-effectiveness ratio was $68 600 per QALY gained (95% UI, $41 800 to $88 900). RESULTS OF SENSITIVITY ANALYSIS: Screening 30-, 40-, and 50-year-old cohorts was cost-effective in 99%, 88%, and 19% of probabilistic simulations, respectively, at a $100 000-per-QALY threshold. The test costs at which screening 30-, 40-, and 50-year-olds reached the $100 000-per-QALY threshold were $413, $290, and $166, respectively. Variant prevalence and adherence to preventive interventions were also highly influential parameters. LIMITATIONS: Population averages for model inputs, which were derived predominantly from European populations, vary across ancestries and health care environments. CONCLUSION: Population genomic screening with a restricted panel of high-evidence genes associated with 3 CDC Tier 1 conditions is likely to be cost-effective in U.S. adults younger than 40 years if the testing cost is relatively low and probands have access to preventive interventions. PRIMARY FUNDING SOURCE: National Human Genome Research Institute.
Assuntos
Doenças Cardiovasculares , Hiperlipoproteinemia Tipo II , Adulto , Humanos , Adulto Jovem , Pessoa de Meia-Idade , Análise de Custo-Efetividade , Análise Custo-Benefício , Metagenômica , Anos de Vida Ajustados por Qualidade de Vida , Programas de RastreamentoRESUMO
Single-cell RNA sequencing (scRNA-seq) data are noisy and sparse. Here, we show that transfer learning across datasets remarkably improves data quality. By coupling a deep autoencoder with a Bayesian model, SAVER-X extracts transferable gene-gene relationships across data from different labs, varying conditions and divergent species, to denoise new target datasets.
Assuntos
Neoplasias da Mama/metabolismo , Biologia Computacional/métodos , Leucócitos Mononucleares/metabolismo , Análise de Sequência de RNA/normas , Análise de Célula Única/métodos , Linfócitos T/metabolismo , Transcriptoma , Animais , Teorema de Bayes , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Camundongos , Análise de Sequência de RNA/métodosRESUMO
PURPOSE: Genomic screening for Lynch syndrome (LS) could prevent colorectal cancer (CRC) by identifying high-risk patients and instituting intensive CRC screening. We estimated the cost-effectiveness of a population-wide LS genomic screening vs family history-based screening alone in an unselected US population. METHODS: We developed a decision-analytic Markov model including health states for precancer, stage-specific CRC, and death and assumed an inexpensive test cost of $200. We conducted sensitivity and threshold analyses to evaluate model uncertainty. RESULTS: Screening unselected 30-year-olds for LS variants resulted in 48 (95% credible range [CR] = 35-63) fewer overall CRC cases per 100,000 screened individuals, leading to 187 quality-adjusted life-years (QALYs; 95% CR = 123-260) gained at an incremental cost of $24.6 million (95% CR = $20.3 million-$29.1 million). The incremental cost-effectiveness ratio was $132,200, with an 8% and 71% probability of being cost-effective at $100,000 and $150,000 per QALY willingness-to-pay thresholds, respectively. CONCLUSION: Population LS screening may be cost-effective in younger patient populations under a $150,000 willingness-to-pay per QALY threshold and with a relatively inexpensive test cost. Further reductions in testing costs and/or the inclusion of LS testing within a broader multiplex screening panel are needed for screening to become highly cost-effective.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Análise Custo-Benefício , Genômica , Humanos , Anos de Vida Ajustados por Qualidade de Vida , Estados Unidos/epidemiologiaRESUMO
Biological self-assembly procedures, which are generally carried out in an aqueous solution, have been found to be the most promising method for directing the fabrication of diverse nanothermites, including Al/CuO nanothermite. However, the aqueous environment in which Al nanoparticles self-assemble has an impact on their stability. We show that using a peptide to self-assemble Al or CuO nanoparticles considerably improves their durability in phosphate buffer aqueous solution, with Al and CuO nanoparticles remaining intact in aqueous solution for over 2 weeks with minimal changes in the structure. When peptide-assembled Al/CuO nanothermite was compared with a physically mixed sample in phosphate buffer for 30 min, the energy release of the former was higher by 26%. Furthermore, the energy release of peptide-assembled Al/CuO nanocomposite in phosphate buffer showed a 6% reduction by Day 7, while that of the peptide-assembled Al/CuO nanocomposite in ultrapure water was reduced by 75%. Taken together, our study provides an easy method for keeping the thermal activity of Al/CuO nanothermite assembled in aqueous solution.
Assuntos
Cobre , Nanocompostos , Cobre/química , Nanocompostos/química , Peptídeos , Fosfatos , ÁguaRESUMO
Current guidelines recommend dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y12 inhibitors following percutaneous coronary intervention (PCI). CYP2C19 genotype can guide DAPT selection, prescribing ticagrelor or prasugrel for loss-of-function (LOF) allele carriers (genotype-guided escalation). Cost-effectiveness analyses (CEA) are traditionally grounded in clinical trial data. We conduct a CEA using real-world data using a 1-year decision-analytic model comparing primary strategies: universal empiric clopidogrel (base case), universal ticagrelor, and genotype-guided escalation. We also explore secondary strategies commonly implemented in practice, wherein all patients are prescribed ticagrelor for 30 days post PCI. After 30 days, all patients are switched to clopidogrel irrespective of genotype (nonguided de-escalation) or to clopidogrel only if patients do not harbor an LOF allele (genotype-guided de-escalation). Compared with universal clopidogrel, both universal ticagrelor and genotype-guided escalation were superior with improvement in quality-adjusted life years (QALY's). Only genotype-guided escalation was cost-effective ($42,365/QALY) and demonstrated the highest probability of being cost-effective across conventional willingness-to-pay thresholds. In the secondary analysis, compared with the nonguided de-escalation strategy, although genotype-guided de-escalation and universal ticagrelor were more effective, with ICER of $188,680/QALY and $678,215/QALY, respectively, they were not cost-effective. CYP2C19 genotype-guided antiplatelet prescribing is cost-effective compared with either universal clopidogrel or universal ticagrelor using real-world implementation data. The secondary analysis suggests genotype-guided and nonguided de-escalation may be viable strategies, needing further evaluation.
Assuntos
Síndrome Coronariana Aguda/economia , Síndrome Coronariana Aguda/terapia , Citocromo P-450 CYP2C19/genética , Custos de Medicamentos , Técnicas de Diagnóstico Molecular/economia , Intervenção Coronária Percutânea , Variantes Farmacogenômicos , Inibidores da Agregação Plaquetária/economia , Inibidores da Agregação Plaquetária/uso terapêutico , Síndrome Coronariana Aguda/genética , Aspirina/economia , Aspirina/uso terapêutico , Clopidogrel/economia , Clopidogrel/uso terapêutico , Análise Custo-Benefício , Técnicas de Apoio para a Decisão , Terapia Antiplaquetária Dupla/economia , Humanos , Intervenção Coronária Percutânea/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos , Valor Preditivo dos Testes , Anos de Vida Ajustados por Qualidade de Vida , Ticagrelor/economia , Ticagrelor/uso terapêutico , Fatores de Tempo , Resultado do TratamentoRESUMO
Motivation: Copy number variations (CNVs) are gains and losses of DNA segments and have been associated with disease. Many large-scale genetic association studies are performing CNV analysis using whole exome sequencing (WES) and whole genome sequencing (WGS). In many of these studies, previous single-nucleotide polymorphism (SNP)-array data are available. An integrated cross-platform analysis is expected to improve resolution and accuracy, yet there is no tool for effectively combining data from sequencing and array platforms. The detection of CNVs using sequencing data alone can also be further improved by the utilization of allele-specific reads. Results: We propose a statistical framework, integrated CNV (iCNV) detection algorithm, which can be applied to multiple study designs: WES only, WGS only, SNP array only, or any combination of SNP and sequencing data. iCNV applies platform-specific normalization, utilizes allele specific reads from sequencing and integrates matched NGS and SNP-array data by a hidden Markov model. We compare integrated two-platform CNV detection using iCNV to naïve intersection or union of platforms and show that iCNV increases sensitivity and robustness. We also assess the accuracy of iCNV on WGS data only and show that the utilization of allele-specific reads improve CNV detection accuracy compared to existing methods. Availability and implementation: https://github.com/zhouzilu/iCNV. Supplementary information: Supplementary data are available at Bioinformatics online.
Assuntos
Variações do Número de Cópias de DNA , Software , Sequenciamento Completo do Genoma/métodos , Algoritmos , Alelos , Genômica/métodos , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Summary: Copy number variation is an important and abundant source of variation in the human genome, which has been associated with a number of diseases, especially cancer. Massively parallel next-generation sequencing allows copy number profiling with fine resolution. Such efforts, however, have met with mixed successes, with setbacks arising partly from the lack of reliable analytical methods to meet the diverse and unique challenges arising from the myriad experimental designs and study goals in genetic studies. In cancer genomics, detection of somatic copy number changes and profiling of allele-specific copy number (ASCN) are complicated by experimental biases and artifacts as well as normal cell contamination and cancer subclone admixture. Furthermore, careful statistical modeling is warranted to reconstruct tumor phylogeny by both somatic ASCN changes and single nucleotide variants. Here we describe a flexible computational pipeline, MARATHON, which integrates multiple related statistical software for copy number profiling and downstream analyses in disease genetic studies. Availability and implementation: MARATHON is publicly available at https://github.com/yuchaojiang/MARATHON. Supplementary information: Supplementary data are available at Bioinformatics online.
Assuntos
Variações do Número de Cópias de DNA , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Modelos Estatísticos , Neoplasias/genética , Análise de Sequência de DNA/métodos , Software , Algoritmos , Genômica/métodos , Humanos , Modelos Genéticos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
XWAS is a new software suite for the analysis of the X chromosome in association studies and similar genetic studies. The X chromosome plays an important role in human disease and traits of many species, especially those with sexually dimorphic characteristics. Special attention needs to be given to its analysis due to the unique inheritance pattern, which leads to analytical complications that have resulted in the majority of genome-wide association studies (GWAS) either not considering X or mishandling it with toolsets that had been designed for non-sex chromosomes. We hence developed XWAS to fill the need for tools that are specially designed for analysis of X. Following extensive, stringent, and X-specific quality control, XWAS offers an array of statistical tests of association, including: 1) the standard test between a SNP (single nucleotide polymorphism) and disease risk, including after first stratifying individuals by sex, 2) a test for a differential effect of a SNP on disease between males and females, 3) motivated by X-inactivation, a test for higher variance of a trait in heterozygous females as compared with homozygous females, and 4) for all tests, a version that allows for combining evidence from all SNPs across a gene. We applied the toolset analysis pipeline to 16 GWAS datasets of immune-related disorders and 7 risk factors of coronary artery disease, and discovered several new X-linked genetic associations. XWAS will provide the tools and incentive for others to incorporate the X chromosome into GWAS and similar studies in any species with an XX/XY system, hence enabling discoveries of novel loci implicated in many diseases and in their sexual dimorphism.
Assuntos
Cromossomos Humanos X/genética , Estudo de Associação Genômica Ampla/métodos , Software , Feminino , Humanos , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Inativação do Cromossomo XRESUMO
PURPOSE: The liver is the most frequent metastatic site for colorectal cancer. Its microenvironment is modified to provide a niche that is conducive for colorectal cancer cell growth. This study focused on characterizing the cellular changes in the metastatic colorectal cancer (mCRC) liver tumor microenvironment (TME). EXPERIMENTAL DESIGN: We analyzed a series of microsatellite stable (MSS) mCRCs to the liver, paired normal liver tissue, and peripheral blood mononuclear cells using single-cell RNA sequencing (scRNA-seq). We validated our findings using multiplexed spatial imaging and bulk gene expression with cell deconvolution. RESULTS: We identified TME-specific SPP1-expressing macrophages with altered metabolism features, foam cell characteristics, and increased activity in extracellular matrix (ECM) organization. SPP1+ macrophages and fibroblasts expressed complementary ligand-receptor pairs with the potential to mutually influence their gene-expression programs. TME lacked dysfunctional CD8 T cells and contained regulatory T cells, indicative of immunosuppression. Spatial imaging validated these cell states in the TME. Moreover, TME macrophages and fibroblasts had close spatial proximity, which is a requirement for intercellular communication and networking. In an independent cohort of mCRCs in the liver, we confirmed the presence of SPP1+ macrophages and fibroblasts using gene-expression data. An increased proportion of TME fibroblasts was associated with the worst prognosis in these patients. CONCLUSIONS: We demonstrated that mCRC in the liver is characterized by transcriptional alterations of macrophages in the TME. Intercellular networking between macrophages and fibroblasts supports colorectal cancer growth in the immunosuppressed metastatic niche in the liver. These features can be used to target immune-checkpoint-resistant MSS tumors.
Assuntos
Neoplasias do Colo , Leucócitos Mononucleares , Neoplasias Hepáticas , Humanos , Neoplasias do Colo/patologia , Fibroblastos , Imunossupressores , Fígado , Macrófagos , Osteopontina , Microambiente Tumoral/genética , Neoplasias Hepáticas/secundárioRESUMO
Magnetic reconnection is a process that can rapidly convert magnetic field energy into plasma thermal energy and kinetic energy, and it is also an important energy conversion mechanism in space physics, astrophysics and plasma physics. Research related to analytical solutions for time-dependent three-dimensional magnetic reconnection is extremely difficult. For decades, several mathematical descriptions have been developed regarding different reconnection mechanisms, in which the equations based on magnetohydrodynamics theory outside the reconnection diffusion region are widely accepted. However, the equation set cannot be analytically solved unless specified constraints are imposed or the equations are reduced. Based on previous analytical methods for kinematic stationary reconnection, here the analytical solutions for time-dependent kinematic three-dimensional magnetic reconnection are discussed. In contrast to the counter-rotating plasma flows that existed in steady-state reconnection, it is found that spiral plasma flows, which have never been reported before, can be generated if the magnetic field changes exponentially with time. These analyses reveal new scenarios for time-dependent kinematic three-dimensional magnetic reconnection, and the deduced analytical solutions could improve our understanding of the dynamics involved in reconnection processes, as well as the interactions between the magnetic field and plasma flows during magnetic reconnection.
Assuntos
Campos Magnéticos , Física , Fenômenos Biomecânicos , Fenômenos Físicos , DifusãoRESUMO
Cell senescence deters the activation of various oncogenes. Induction of senescence is, therefore, a potentially effective strategy to interfere with vital processes in tumor cells. Sphingosine-1-phosphate receptor 1 (S1PR1) has been implicated in various cancer types, including ovarian cancer. The mechanism by which S1PR1 regulates ovarian cancer cell senescence is currently elusive. In this study, we demonstrate that S1PR1 was highly expressed in human ovarian cancer tissues and cell lines. S1PR1 deletion inhibited the proliferation and migration of ovarian cancer cells. S1PR1 deletion promoted ovarian cancer cell senescence and sensitized ovarian cancer cells to cisplatin chemotherapy. Exposure of ovarian cancer cells to sphingosine-1-phosphate (S1P) increased the expression of 3-phosphatidylinositol-dependent protein kinase 1 (PDK1), decreased the expression of large tumor suppressor 1/2 (LATS1/2), and induced phosphorylation of Yes-associated protein (p-YAP). Opposite results were obtained in S1PR1 knockout cells following pharmacological inhibition. After silencing LATS1/2 in S1PR1-deficient ovarian cancer cells, senescence was suppressed and S1PR1 expression was increased concomitantly with YAP expression. Transcriptional regulation of S1PR1 by YAP was confirmed by chromatin immunoprecipitation. Accordingly, the S1PR1-PDK1-LATS1/2-YAP pathway regulates ovarian cancer cell senescence and does so through a YAP-mediated feedback loop. S1PR1 constitutes a druggable target for the induction of senescence in ovarian cancer cells. Pharmacological intervention in the S1PR1-PDK1-LATS1/2-YAP signaling axis may augment the efficacy of standard chemotherapy.
Assuntos
Neoplasias Ovarianas , Proteínas Quinases , Feminino , Humanos , Receptores de Esfingosina-1-Fosfato/genética , Neoplasias Ovarianas/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Senescência Celular/genética , Proliferação de Células/genéticaRESUMO
To coordinate Medicare and Medicaid benefits, multiple states are creating opportunities for dual-eligible beneficiaries to join Medicare Advantage Dual-Eligible Special Needs Plans (D-SNPs) and Medicaid plans operated by the same insurer. Tennessee implemented this approach by requiring insurers who offered Medicaid plans to also offer a D-SNP by 2015. Tennessee's aligned D-SNP participation increased from 7% to 24% of dual-eligible beneficiaries aged 65 years and above between 2011 and 2017. Within a county, a 10-percentage-point increase in aligned D-SNP participation was associated with 0.3 fewer inpatient admissions (p = .048), 13.9 fewer prescription drugs per month (p = .048), and 0.3 fewer nursing home users (p = .06) per 100 dual-eligible beneficiaries aged 65 years and older. Increased aligned plan participation was associated with 0.2 more inpatient admissions (p = .004) per 100 dual-eligible beneficiaries younger than 65 years. For some dual-eligible beneficiaries, increasing Medicare and Medicaid managed plan alignment has the potential to promote more efficient service use.
Assuntos
Medicare Part C , Medicamentos sob Prescrição , Idoso , Definição da Elegibilidade , Humanos , Programas de Assistência Gerenciada , Medicaid , Estados UnidosRESUMO
We discuss tradeoffs and errors associated with approaches to modeling health economic decisions. Through an application in pharmacogenomic (PGx) testing to guide drug selection for individuals with a genetic variant, we assessed model accuracy, optimal decisions, and computation time for an identical decision scenario modeled 4 ways: using 1) coupled-time differential equations (DEQ), 2) a cohort-based discrete-time state transition model (MARKOV), 3) an individual discrete-time state transition microsimulation model (MICROSIM), and 4) discrete event simulation (DES). Relative to DEQ, the net monetary benefit for PGx testing (v. a reference strategy of no testing) based on MARKOV with rate-to-probability conversions using commonly used formulas resulted in different optimal decisions. MARKOV was nearly identical to DEQ when transition probabilities were embedded using a transition intensity matrix. Among stochastic models, DES model outputs converged to DEQ with substantially fewer simulated patients (1 million) v. MICROSIM (1 billion). Overall, properly embedded Markov models provided the most favorable mix of accuracy and runtime but introduced additional complexity for calculating cost and quality-adjusted life year outcomes due to the inclusion of "jumpover" states after proper embedding of transition probabilities. Among stochastic models, DES offered the most favorable mix of accuracy, reliability, and speed.
Assuntos
Tecnologia Biomédica , Técnicas de Apoio para a Decisão , Análise Custo-Benefício , Humanos , Cadeias de Markov , Políticas , Reprodutibilidade dos TestesRESUMO
Although scRNA-seq is now ubiquitously adopted in studies of intratumor heterogeneity, detection of somatic mutations and inference of clonal membership from scRNA-seq is currently unreliable. We propose DENDRO, an analysis method for scRNA-seq data that clusters single cells into genetically distinct subclones and reconstructs the phylogenetic tree relating the subclones. DENDRO utilizes transcribed point mutations and accounts for technical noise and expression stochasticity. We benchmark DENDRO and demonstrate its application on simulation data and real data from three cancer types. In particular, on a mouse melanoma model in response to immunotherapy, DENDRO delineates the role of neoantigens in treatment response.
Assuntos
Heterogeneidade Genética , Técnicas Genéticas , Neoplasias/genética , Filogenia , Software , Animais , Humanos , Camundongos , Análise de Célula ÚnicaRESUMO
While single cell RNA sequencing (scRNA-seq) is invaluable for studying cell populations, cell-surface proteins are often integral markers of cellular function and serve as primary targets for therapeutic intervention. Here we propose a transfer learning framework, single cell Transcriptome to Protein prediction with deep neural network (cTP-net), to impute surface protein abundances from scRNA-seq data by learning from existing single-cell multi-omic resources.
Assuntos
Células/metabolismo , Perfilação da Expressão Gênica/métodos , Proteínas de Membrana/genética , Análise de Célula Única/métodos , Transcriptoma , Células/citologia , Humanos , Proteínas de Membrana/metabolismo , Redes Neurais de Computação , Análise de Sequência de RNARESUMO
Importance: Little is known about the breadth of health care networks or the degree to which different insurers' networks overlap. Objective: To quantify network breadth and exclusivity (ie, overlap) among primary care physician (PCP), cardiology, and general acute care hospital networks for employer-based (large group and small group), individually purchased (marketplace), Medicare Advantage (MA), and Medicaid managed care (MMC) plans. Design, Setting, and Participants: This cross-sectional study included 1192 networks from Vericred. The analytic unit was the network-zip code-clinician type-market, which captured attributes of networks from the perspective of a hypothetical patient seeking access to in-network clinicians or hospitals within a 60-minute drive. Exposures: Enrollment in a private insurance plan. Main Outcomes and Measures: Percentage of in-network physicians and/or hospitals within a 60-minute drive from a hypothetical patient in a given zip code (breadth). Number of physicians and/or hospitals within each network that overlapped with other insurers' networks, expressed as a percentage of the total possible number of shared connections (exclusivity). Descriptive statistics (mean, quantiles) were produced overall and by network breadth category, as follows: extra-small (<10%), small (10%-25%), medium (25%-40%), large (40%-60%), and extra-large (>60%). Networks were analyzed by insurance type, state, and insurance, physician, and/or hospital market concentration level, as measured by the Hirschman-Herfindahl index. Results: Across all US zip code-network observations, 415â¯549 of 511â¯143 large-group PCP networks (81%) were large or extra-large compared with 138â¯485 of 202â¯702 MA (68%), 191â¯918 of 318â¯082 small-group (60%), 60â¯425 of 149â¯841 marketplace (40%), and 21â¯781 of 66â¯370 MMC (40%) networks. Large-group employer networks had broader coverage than all other network plans (mean [SD] PCP breadth: large-group employer-based plans, 57.3% [20.1]; small-group employer-based plans, 45.7% [21.4]; marketplace, 36,4% [21.2]; MMC, 32.3% [19.3]; MA, 47.4% [18.3]). MMC networks were the least exclusive (a mean [SD] overlap of 61.3% [10.5] for PCPs, 66.5% [9.8] for cardiology, and 60.2% [12.3] for hospitals). Networks were narrowest (mean [SD] breadth 42.4% [16.9]) and most exclusive (mean [SD] overlap 47.7% [23.0]) in California and broadest (79.9% [16.6]) and least exclusive (71.1% [14.6]) in Nebraska. Rising levels of insurer and market concentration were associated with broader and less exclusive networks. Markets with concentrated primary care and insurance markets had the broadest (median [interquartile range {IQR}], 75.0% [60.0%-83.1%]) and least exclusive (median [IQR], 63.7% [52.4%-73.7%]) primary care networks among large-group commercial plans, while markets with least concentration had the narrowest (median [IQR], 54.6% [46.8%-67.6%]) and most exclusive (median [IQR], 49.4% [41.9%-56.9%]) networks. Conclusions and Relevance: In this study, narrower health care networks had a relatively large degree of overlap with other networks in the same geographic area, while broader networks were associated with physician, hospital, and insurance market concentration. These results suggest that many patients could switch to a lower-cost, narrow network plan without losing in-network access to their PCP, although future research is needed to assess the implications for care quality and clinical integration across in-network health care professionals and facilities in narrow network plans.
Assuntos
Redes Comunitárias , Prestação Integrada de Cuidados de Saúde/organização & administração , Setor de Assistência à Saúde/organização & administração , Instituições Privadas de Saúde/normas , Seguro Saúde/organização & administração , Redes Comunitárias/estatística & dados numéricos , Redes Comunitárias/provisão & distribuição , Estudos Transversais , Sistemas de Informação em Saúde , Humanos , Atenção Primária à Saúde/organização & administração , Garantia da Qualidade dos Cuidados de Saúde , Estados UnidosRESUMO
Importance: Genomic screening for hereditary breast and ovarian cancer (HBOC) in unselected women offers an opportunity to prevent cancer morbidity and mortality, but the potential clinical impact and cost-effectiveness of such screening have not been well studied. Objective: To estimate the lifetime incremental incidence of HBOC and the quality-adjusted life-years (QALYs), costs, and cost-effectiveness of HBOC genomic screening in an unselected population vs family history-based testing. Design, Setting, and Participants: In this study conducted from October 27, 2017, to May 3, 2020, a decision analytic Markov model was developed that included health states for precancer, for risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO), for earlier- and later-stage HBOC, after cancer, and for death. A complimentary cascade testing module was also developed to estimate outcomes in first-degree relatives. Age-specific RRM and RRSO uptake probabilities were estimated from the Geisinger MyCode Community Health Initiative and published sources. Parameters including RRM and RRSO effectiveness, variant-specific cancer risk, costs, and utilities were derived from published sources. Sensitivity and scenario analyses were conducted to evaluate model assumptions and uncertainty. Main Outcomes and Measures: Lifetime cancer incidence, QALYs, life-years, and direct medical costs for genomic screening in an unselected population vs family history-based testing only were calculated. The incremental cost-effectiveness ratio (ICER) was calculated as the difference in cost between strategies divided by the difference in QALYs between strategies. Earlier-stage and later-stage cancer cases prevented and total cancer cases prevented were also calculated. Results: The model found that population screening of 30-year-old women was associated with 75 (95% credible range [CR], 60-90) fewer overall cancer cases and 288 QALYs (95% CR, 212-373 QALYs) gained per 100â¯000 women screened, at an incremental cost of $25 million (95% CR, $21 millon to $30 million) vs family history-based testing; the ICER was $87â¯700 (78% probability of being cost-effective at a threshold of $100â¯000 per QALY). In contrast, population screening of 45-year-old women was associated with 24 (95% CR, 18-29) fewer cancer cases and 97 QALYs (95% CR, 66-130 QALYs) gained per 100â¯000 women screened, at an incremental cost of $26 million (95% CR, $22 million to $30 million); the ICER was $268â¯200 (0% probability of being cost-effective at a threshold of $100â¯000 per QALY). A scenario analysis without cascade testing increased the ICER to $92â¯600 for 30-year-old women and $354â¯500 for 45-year-old women. A scenario analysis assuming a 5% absolute decrease in mammography screening in women without a variant was associated with the potential for net harm (-90 QALYs per 100â¯000 women screened; 95% CR, -180 to 10 QALYs). Conclusions and Relevance: The results of this study suggest that population HBOC screening may be cost-effective among younger women but not among older women. Cascade testing of first-degree relatives added a modest improvement in clinical and economic value. The potential for harm conferred by inappropriate reduction in mammography among noncarriers should be quantified.
Assuntos
Neoplasias da Mama/diagnóstico , Análise Custo-Benefício/métodos , Programas de Rastreamento/economia , Neoplasias Ovarianas/diagnóstico , Adulto , Análise Custo-Benefício/tendências , Feminino , Predisposição Genética para Doença , Humanos , Incidência , Programas de Rastreamento/métodos , Programas de Rastreamento/tendências , Pessoa de Meia-Idade , Anos de Vida Ajustados por Qualidade de Vida , Estados UnidosRESUMO
We discuss a decision-theoretic approach to building a panel-based, preemptive genotyping program. The method is based on findings that a large percentage of patients are prescribed medications that are known to have pharmacogenetic associations, and over time, a substantial proportion are prescribed additional such medication. Preemptive genotyping facilitates genotype-guided therapy at the time medications are prescribed; panel-based testing allows providers to reuse previously collected genetic data when a new indication arises. Because it is cost-prohibitive to conduct panel-based genotyping on all patients, we describe a three-step approach to identify patients with the highest anticipated benefit. First, we construct prediction models to estimate the risk of being prescribed one of the target medications using readily available clinical data. Second, we use literature-based estimates of adverse event rates, variant allele frequencies, secular death rates, and costs to construct a discrete event simulation that estimates the expected benefit of having an individual's genetic data in the electronic health record after an indication has occurred. Finally, we combine medication prescription risk with expected benefit of genotyping once a medication is indicated to calculate the expected benefit of preemptive genotyping. For each patient-clinic visit, we calculate this expected benefit across a range of medications and select patients with the highest expected benefit overall. We build a proof of concept implementation using a cohort of patients from a single academic medical center observed from July 2010 through December 2012. We then apply the results of our modeling strategy to show the extent to which we can improve clinical and economic outcomes in a cohort observed from January 2013 through December 2015.
RESUMO
Colonic tissues in Inflammatory Bowel Disease (IBD) patients exhibit oxygen deprivation and activation of hypoxia-inducible factor 1α and 2α (HIF-1α and HIF-2α), which mediate cellular adaptation to hypoxic stress. Notably, macrophages and neutrophils accumulate preferentially in hypoxic regions of the inflamed colon, suggesting that myeloid cell functions in colitis are HIF-dependent. By depleting ARNT (the obligate heterodimeric binding partner for both HIFα subunits) in a murine model, we demonstrate here that myeloid HIF signaling promotes the resolution of acute colitis. Specifically, myeloid pan-HIF deficiency exacerbates infiltration of pro-inflammatory neutrophils and Ly6C+ monocytic cells into diseased tissue. Myeloid HIF ablation also hinders macrophage functional conversion to a protective, pro-resolving phenotype, and elevates gut serum amyloid A levels during the resolution phase of colitis. Therefore, myeloid cell HIF signaling is required for efficient resolution of inflammatory damage in colitis, implicating serum amyloid A in this process.