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2.
Stat Med ; 40(8): 2037-2054, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33540472

RESUMO

Development of cancer screening biomarkers usually follows the Early Detection Research Network 5-Phase guideline in Pepe et al. A key feature of this guide is that the phased development follows a sequential order, moving to the next phase only when the current phase study is complete and has met its target performance. Motivated by a newly funded Newly onset Diabetes cohort study, we propose a design evaluating new biomarkers to discriminate between cases and controls in the presence of an existing screening test. The proposed design achieves two goals: (1) avoiding bias in estimating sensitivity or specificity in predicting cancer at a given time period prior to clinical diagnosis, using data from both screening detected cancers in Phase IV study and clinically diagnosed cancers in Phase III study; and (2) building a panel with biomarkers for Phase III and IV studies based on all data. A simulation study shows that the proposed design outperforms both a conventional method using data in Phase III arm only and a naive method using data in Phase III and IV arms ignoring the difference between the time of screening the detected cancer and the time of clinical diagnosis. The proposed design yields a smaller standard error of the estimation and increases the statistical power to confirm biomarker performance. This proposed method has the potential to shorten the cancer screening biomarker development process, use resources more effectively, and bring benefits to patients quickly.

3.
Stat Med ; 40(7): 1767-1789, 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33530129

RESUMO

During the early stage of biomarker discovery, high throughput technologies allow for simultaneous input of thousands of biomarkers that attempt to discriminate between healthy and diseased subjects. In such cases, proper ranking of biomarkers is highly important. Common measures, such as the area under the receiver operating characteristic (ROC) curve (AUC), as well as affordable sensitivity and specificity levels, are often taken into consideration. Strictly speaking, such measures are appropriate under a stochastic ordering assumption, which implies, without loss of generality, that higher measurements are more indicative for the disease. Such an assumption is not always plausible and may lead to rejection of extremely useful biomarkers at this early discovery stage. We explore the length of a smooth ROC curve as a measure for biomarker ranking, which is not subject to directionality. We show that the length corresponds to a ϕ divergence, is identical to the corresponding length of the optimal (likelihood ratio) ROC curve, and is an appropriate measure for ranking biomarkers. We explore the relationship between the length measure and the AUC of the optimal ROC curve. We then provide a complete framework for the evaluation of a biomarker in terms of sensitivity and specificity through a proposed ROC analogue for use in improper settings. In the absence of any clinical insight regarding the appropriate cutoffs, we estimate the sensitivity and specificity under a two-cutoff extension of the Youden index and we further take into account the implied costs. We apply our approaches on two biomarker studies that relate to pancreatic and esophageal cancer.

4.
Cancer Epidemiol Biomarkers Prev ; 29(12): 2575-2582, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33172885

RESUMO

The cancer early-detection biomarker field was, compared with the therapeutic arena, in its infancy when the Early Detection Research Network (EDRN) was initiated in 2000. The EDRN has played a crucial role in changing the culture and the ways people conduct biomarker studies. The EDRN proposed biomarker developmental guidelines and biomarker pivotal trial study design standards, created biomarker reference sets and functioned as an unbiased broker for the field, implemented the most rigorous blinding policy in the biomarker field, developed an array of statistical and computational tools for early-detection biomarker evaluations, and developed a multidisciplinary team-science approach. We reviewed these contributions made by the EDRN and their impacts on maturing the field. Future challenges and opportunities in cancer early-detection biomarker translational research are discussed, particularly in strengthening biomarker discovery pipeline and conducting more efficient biomarker validation studies.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."

5.
J Thorac Oncol ; 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33137463

RESUMO

RATIONALE: The workup and longitudinal monitoring for subjects presenting with pulmonary nodules is a pressing clinical problem. A blood-based biomarker panel potentially has utility for identifying subjects at higher risk for harboring a malignant nodule for whom additional work-up would be indicated or subjects at reduced risk for whom imaging based follow-up would be indicated. OBJECTIVES: To assess whether a previously described four-protein biomarker panel, previously reported to improve assessment of lung cancer risk compared to a smoking-based lung cancer risk model, can provide discrimination between benign and malignant indeterminate pulmonary nodules. METHODS: A previously validated multiplex enzyme linked immunoassay was performed on matched case and control samples from each cohort. MEASUREMENTS: The biomarker panel was tested in two case-control cohorts of patients presenting with indeterminate pulmonary nodules at the University of Pittsburgh Medical Center and The University of Texas Southwestern. MAIN RESULTS: In both cohorts, the biomarker panel resulted in improved prediction of lung cancer risk over a model based on nodule size alone. Of particular note, the addition of the marker panel to nodule size greatly improved sensitivity at a high specificity in both cohorts. CONCLUSIONS: A four-marker biomarker panel, previously validated to improve lung cancer risk prediction, also shows utility in distinguishing benign from malignant indeterminate pulmonary nodules. Its performance in improving sensitivity at a high specificity indicates potential utility of the marker panel in assessing likelihood of malignancy in otherwise indeterminate nodules.

6.
Artigo em Inglês | MEDLINE | ID: mdl-32961340

RESUMO

Hepatocellular carcinoma (HCC) continues to have a dismal prognosis, with 5-year survival below 20%. This poor prognosis can be in part attributed to failures along the cancer screening process continuum such as underuse of screening in at risk patients and appropriate treatments for patients with HCC. Better understanding these process failures, and how they compare to those seen in other cancer types, can help inform potential intervention targets and strategies to reduce HCC-related mortality. Herein, we outline a conceptual model with several discrete steps in the HCC screening process continuum including risk assessment, screening initiation, follow-up of screening results, diagnostic evaluation, and treatment evaluation. The conceptual model illustrates how each step in the screening process is prone to delays or failure, resulting in worse outcomes such as late stage diagnosis or poor survival, and how factors at the patient, provider, and health care system levels can contribute to these failures. We compare cancer screening processes for HCC with those employed in breast and colorectal cancer screening to identify opportunities for improvement. The Translational Liver Cancer consortium was recently established by the National Cancer Institute with the goal of improving early detection of HCC. Studies designed to address failures in the HCC screening process continuum will help accomplish this goal.

7.
Cancer Cell ; 2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-32976775

RESUMO

Cancer biomarker research has become a data-intensive discipline requiring innovative approaches for data analysis that can combine traditional and data-driven methods. Significant leveraging can be done transferring methodologies and capabilities across scientific disciplines, such as planetary science and astronomy, each of which are grappling with and developing similar solutions for the analysis of massive scientific data.

8.
Cancers (Basel) ; 12(8)2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32722209

RESUMO

Mutations identified in the epidermal growth factor receptor (EGFR) predict sensitivity to EGFR-targeted therapy for non-small cell lung carcinoma (NSCLC). We previously reported that Electric Field-Induced Release and Measurement (EFIRM)-based liquid biopsy could detect EGFR ctDNA with >94% concordance with tissue-based genotyping. A side-by-side comparison of concordance of EFIRM and droplet digital PCR (ddPCR) for the detection of the two front-line actionable EFGR mutations was performed with paired plasma and saliva samples from 13 NSCLC patients. Deep sequencing analysis based on single-strand DNA library preparation was employed to determine the size distributions of EGFR L858R ctDNA in plasma and saliva samples. EFIRM detected both EGFR mutations with 100% sensitivity in both plasma and saliva samples, whereas ddPCR detected EGFR mutations with sensitivities of 84.6% and 15.4%, respectively. In saliva samples, the majority of EGFR L858R ctDNA fragments detected were <80 bp. Deep sequencing analysis of ctDNA enriched for the EGFR L858R mutation revealed the significant presence of EGFR L858R ctDNA as ultra-short circulating tumor DNA (usctDNA) with the size of 40-60 bp in patient plasma and saliva. Most of usctDNAs are not amplifiable with the current ddPCR assay. Further examination using cell lines and patient biofluids revealed that the majority of usctDNAs were predominately localized in the exosomal fraction. Our study revealed the abundant existence of EGFR ctDNA in the plasma and saliva of NSCLC patients is usctDNA. usctDNA is a novel type of targets for liquid biopsy that can be efficiently detected by EFIRM technology.

9.
PLoS Genet ; 16(3): e1008667, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32226005

RESUMO

Genome-wide association studies have identified more than 100 SNPs that increase the risk of prostate cancer (PrCa). We identify and compare expression quantitative trait loci (eQTLs) and CpG methylation quantitative trait loci (meQTLs) among 147 established PrCa risk SNPs in primary prostate tumors (n = 355 from a Seattle-based study and n = 495 from The Cancer Genome Atlas, TCGA) and tumor-adjacent, histologically benign samples (n = 471 from a Mayo Clinic study). The role of DNA methylation in eQTL regulation of gene expression was investigated by data triangulation using several causal inference approaches, including a proposed adaptation of the Causal Inference Test (CIT) for causal direction. Comparing eQTLs between tumors and benign samples, we show that 98 of the 147 risk SNPs were identified as eQTLs in the tumor-adjacent benign samples, and almost all 34 eQTL identified in tumor sets were also eQTLs in the benign samples. Three lines of results support the causal role of DNA methylation. First, nearly 100 of the 147 risk SNPs were identified as meQTLs in one tumor set, and almost all eQTLs in tumors were meQTLs. Second, the loss of eQTLs in tumors relative to benign samples was associated with altered DNA methylation. Third, among risk SNPs identified as both eQTLs and meQTLs, mediation analyses suggest that over two-thirds have evidence of a causal role for DNA methylation, mostly mediating genetic influence on gene expression. In summary, we provide a comprehensive catalog of eQTLs, meQTLs and putative cancer genes for known PrCa risk SNPs. We observe that a substantial portion of germline eQTL regulatory mechanisms are maintained in the tumor development, despite somatic alterations in tumor genome. Finally, our mediation analyses illuminate the likely intermediary role of CpG methylation in eQTL regulation of gene expression.


Assuntos
Metilação de DNA/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias da Próstata/genética , Bases de Dados Genéticas , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Fatores de Risco
11.
Prostate Cancer Prostatic Dis ; 23(3): 494-506, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32071439

RESUMO

BACKGROUNDS: Aside from Gleason score few factors accurately identify the subset of prostate cancer (PCa) patients at high risk for metastatic progression. We hypothesized that copy number alterations (CNAs), assessed using CpG methylation probes on Illumina Infinium® Human Methylation450 (HM450K) BeadChip arrays, could identify primary prostate tumors with potential to develop metastatic progression. METHODS: Epigenome-wide DNA methylation profiling was performed in surgically resected primary tumor tissues from two cohorts of PCa patients with clinically localized disease who underwent radical prostatectomy (RP) as primary therapy and were followed prospectively for at least 5 years: (1) a Fred Hutchinson (FH) Cancer Research Center-based cohort (n = 323 patients); and (2) an Eastern Virginia (EV) Medical School-based cohort (n = 78 patients). CNAs were identified using the R package ChAMP. Metastasis was confirmed by positive bone scan, MRI, CT or biopsy, and death certificates confirmed cause of death. RESULTS: We detected 15 recurrent CNAs were associated with metastasis in the FH cohort and replicated in the EV cohort (p < 0.05) without adjusting for Gleason score in the model. Eleven of the recurrent CNAs were associated with metastatic progression in the FH cohort and validated in the EV cohort (p < 0.05) when adjusting for Gleason score. CONCLUSIONS: This study shows that CNAs can be reliably detected from HM450K-based DNA methylation data. There are 11 recurrent CNAs showing association with metastatic-lethal events following RP and improving prediction over Gleason score. Genes affected by these CNAs may functionally relate to tumor aggressiveness and metastatic progression.

12.
Stat Methods Med Res ; 29(8): 2328-2343, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31868119

RESUMO

Two-phase sampling designs, including nested case-control and case-cohort designs, are frequently utilized in large cohort studies involving expensive biomarkers. To analyze data from two-phase designs with a binary outcome, parametric models such as logistic regression are often adopted. However, when the model assumptions are not valid, parametric models may lead to biased estimation and risk evaluation. In this paper, we propose a robust semiparametric regression model for binary outcomes and an easy-to-implement computational procedure that combines the pool-adjacent violators algorithm with inverse probability weighting. The asymptotic properties are established, including consistency and the convergence rate. Simulation studies show that the proposed method performs well and is more robust than logistic regression methods. We demonstrate the application of the proposed method to real data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.

14.
Cancer Health Disparities ; 3: e1-e15, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31528846

RESUMO

Korean Americans report the lowest and declined rates of colorectal cancer (CRC) screening, compared to general population in the United States. The present study aimed to evaluate the efficacy of a community-based multifaceted intervention designed to improve CRC screening among Korean Americans. A cluster-randomized trial involving 30 Korean church-based community organizations (n = 925) was conducted. Fifteen churches were assigned to intervention (n=470) and the other 15 to control (n = 455) groups. Main components of the intervention included interactive group education, patient navigation, physician engagement, and provision of fecal immunochemical test (FIT) kit. CRC screening rates were assessed at a 12-month follow-up. Participants in the intervention group were significantly more likely to receive CRC screening (69.3%) as compared with those in the control group (16%). The intervention was particularly effective in promoting FIT among the more disadvantaged individuals in the Korean American community. Regression analysis revealed that controlling for the intervention effect, male gender, high school education, annual income of $20,000-40,000 were significantly associated with increased screening by FIT, whereas English inefficiency was significantly and lack of health insurance was marginally significantly associated with decreased screening by colonoscopy/sigmoidoscopy. Culturally and linguistically appropriate multifaceted intervention combining FIT provision with community-clinical linkage has a potential to be a cost-effective and practical approach to effectively targeting hard-to-reach disadvantaged minority populations and enhance CRC screening to reduce cancer disparities.

15.
Prostate ; 79(14): 1589-1596, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31376183

RESUMO

BACKGROUND: Molecular studies have tried to address the unmet need for prognostic biomarkers in prostate cancer (PCa). Some gene expression tests improve upon clinical factors for prediction of outcomes, but additional tools for accurate prediction of tumor aggressiveness are needed. METHODS: Based on a previously published panel of 23 gene transcripts that distinguished patients with metastatic progression, we constructed a prediction model using independent training and testing datasets. Using the validated messenger RNAs and Gleason score (GS), we performed model selection in the training set to define a final locked model to classify patients who developed metastatic-lethal events from those who remained recurrence-free. In an independent testing dataset, we compared our locked model to established clinical prognostic factors and utilized Kaplan-Meier curves and receiver operating characteristic analyses to evaluate the model's performance. RESULTS: Thirteen of 23 previously identified gene transcripts that stratified patients with aggressive PCa were validated in the training dataset. These biomarkers plus GS were used to develop a four-gene (CST2, FBLN1, TNFRSF19, and ZNF704) transcript (4GT) score that was significantly higher in patients who progressed to metastatic-lethal events compared to those without recurrence in the testing dataset (P = 5.7 × 10-11 ). The 4GT score provided higher prediction accuracy (area under the ROC curve [AUC] = 0.76; 95% confidence interval [CI] = 0.69-0.83; partial area under the ROC curve [pAUC] = 0.008) than GS alone (AUC = 0.63; 95% CI = 0.56-0.70; pAUC = 0.002), and it improved risk stratification in subgroups defined by a combination of clinicopathological features (ie, Cancer of the Prostate Risk Assessment-Surgery). CONCLUSION: Our validated 4GT score has prognostic value for metastatic-lethal progression in men treated for localized PCa and warrants further evaluation for its clinical utility.


Assuntos
Biomarcadores Tumorais/genética , Proteínas de Ligação ao Cálcio/genética , Metástase Neoplásica/genética , Neoplasias da Próstata/genética , Receptores do Fator de Necrose Tumoral/genética , Cistatinas Salivares/genética , Fatores Genéricos de Transcrição/genética , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica/patologia , Prognóstico , Neoplasias da Próstata/patologia , RNA Mensageiro/análise , Curva ROC , Medição de Risco , Sensibilidade e Especificidade
16.
Biostatistics ; 2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31420985

RESUMO

Candidate biomarkers discovered in the laboratory need to be rigorously validated before advancing to clinical application. However, it is often expensive and time-consuming to collect the high quality specimens needed for validation; moreover, such specimens are often limited in volume. The Early Detection Research Network has developed valuable specimen reference sets that can be used by multiple labs for biomarker validation. To optimize the chance of successful validation, it is critical to efficiently utilize the limited specimens in these reference sets on promising candidate biomarkers. Towards this end, we propose a novel two-stage validation strategy that partitions the samples in the reference set into two groups for sequential validation. The proposed strategy adopts the group sequential testing method to control for the type I error rate and rotates group membership to maximize the usage of available samples. We develop analytical formulas for performance parameters of this strategy in terms of the expected numbers of biomarkers that can be evaluated and the truly useful biomarkers that can be successfully validated, which can provide valuable guidance for future study design. The performance of our proposed strategy for validating biomarkers with respect to the points on the receiver operating characteristic curve are evaluated via extensive simulation studies and compared with the default strategy of validating each biomarker using all samples in the reference set. Different types of early stopping rules and boundary shapes in the group sequential testing method are considered. Compared with the default strategy, our proposed strategy makes more efficient use of the limited resources in the reference set by allowing more candidate biomarkers to be evaluated, giving a better chance of having truly useful biomarkers successfully validated.

17.
J Community Health ; 44(3): 525-533, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30915676

RESUMO

Low cervical cancer screening rates among Vietnamese American women have been attributed, in part, to inadequate knowledge about cervical cancer and health beliefs that hinder screening. A community-based educational program was developed to improve knowledge and attitudes toward cervical cancer screening in this underserved population. It was hypothesized that the program would result in increases in knowledge, as well as enhanced health beliefs and self-efficacy toward obtaining cervical cancer screening. Using a group-randomized design, 1488 women from 30 Vietnamese community-based organizations were assigned to either the intervention (n = 816) or control (n = 672) conditions. The intervention group received cervical cancer education delivered by bilingual community health educators. Intervention content addressed individual beliefs and expectancies regarding cervical cancer screening (e.g., perceived risk of developing cervical cancer; perceived benefits and barriers to screening; social and cultural norms regarding screening). The control group received general health education, including information about cancer screening. Knowledge and health beliefs were assessed at baseline and post-intervention. Among women in the intervention group, overall knowledge about cervical cancer and screening guidelines increased from pre- to post-program (30% vs. 88%, p < 0.001), perceived benefits of screening increased (3.50 vs. 4.49, p < 0.001), and perceived barriers to screening decreased (3.13 vs. 2.25, p < 0.001). Changes in knowledge and health beliefs were not observed among women in the control group. A community-based educational program can help increase knowledge about cervical cancer and screening, promote positive changes in women's beliefs about the benefits of cervical cancer screening, and reduce perceived barriers to screening. Such programs may play an important role in addressing health disparities and informing underserved populations about recommended screening tests.


Assuntos
Americanos Asiáticos/educação , Detecção Precoce de Câncer/psicologia , Educação em Saúde/organização & administração , Conhecimentos, Atitudes e Prática em Saúde/etnologia , Neoplasias do Colo do Útero/etnologia , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Autoeficácia , Fatores Socioeconômicos , Estados Unidos/epidemiologia , Neoplasias do Colo do Útero/prevenção & controle , Vietnã/etnologia
18.
Am J Gastroenterol ; 114(3): 530-532, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30699099

RESUMO

OBJECTIVES: The Texas Hepatocellular Carcinoma Consortium cohort study investigates risk factors of hepatocellular carcinoma (HCC) and biomarkers for early HCC detection in patients with liver cirrhosis. METHODS: Adult patients with liver cirrhosis are enrolled at 5 clinical centers from 3 cities in Texas, with a target of 5,000 patients. Clinical history, risk factor questionnaires, liver imaging, laboratory data, and blood samples were collected at enrollment and at each 6-month follow-up visit. RESULTS: The primary outcome was the development of HCC. Biomarkers were tested in banked blood samples using prospective specimen collection, retrospective blinded evaluation design. CONCLUSIONS: We describe study design, eligibility criteria, recruitment, study cores, and sample size and analysis considerations.


Assuntos
Carcinoma Hepatocelular/diagnóstico , Cirrose Hepática/diagnóstico por imagem , Neoplasias Hepáticas/diagnóstico , Biomarcadores/metabolismo , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/metabolismo , Estudos de Coortes , Detecção Precoce de Câncer , Mutação em Linhagem Germinativa , Hemoglobina A Glicada/metabolismo , Humanos , Inflamação/metabolismo , Cirrose Hepática/epidemiologia , Cirrose Hepática/metabolismo , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/metabolismo , Síndrome Metabólica/epidemiologia , Obesidade/epidemiologia , Estudos Prospectivos , Texas , Triglicerídeos/metabolismo
19.
Nat Commun ; 10(1): 254, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30651550

RESUMO

Although B cell response is frequently found in cancer, there is little evidence that it alters tumor development or progression. The process through which tumor-associated antigens trigger humoral response is not well delineated. We investigate the repertoire of antigens associated with humoral immune response in pancreatic ductal adenocarcinoma (PDAC) using in-depth proteomic profiling of immunoglobulin-bound proteins from PDAC patient plasmas and identify tumor antigens that induce antibody response together with exosome hallmark proteins. Additional profiling of PDAC cell-derived exosomes reveals significant overlap in their protein content with immunoglobulin-bound proteins in PDAC plasmas, and significant autoantibody reactivity is observed between PDAC cell-derived exosomes and patient plasmas compared to healthy controls. Importantly, PDAC-derived exosomes induce a dose-dependent inhibition of PDAC serum-mediated complement-dependent cytotoxicity towards cancer cells. In summary, we provide evidence that exosomes display a large repertoire of tumor antigens that induce autoantibodies and exert a decoy function against complement-mediated cytotoxicity.


Assuntos
Formação de Anticorpos/imunologia , Antígenos de Neoplasias/imunologia , Linfócitos B/imunologia , Carcinoma Ductal Pancreático/imunologia , Proteínas do Sistema Complemento/imunologia , Exossomos/imunologia , Neoplasias Pancreáticas/imunologia , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/metabolismo , Autoanticorpos/imunologia , Carcinoma Ductal Pancreático/sangue , Linhagem Celular Tumoral , Estudos de Coortes , Conjuntos de Dados como Assunto , Exossomos/metabolismo , Exossomos/ultraestrutura , Feminino , Perfilação da Expressão Gênica , Voluntários Saudáveis , Humanos , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Neoplasias Pancreáticas/sangue , Proteômica/métodos , Análise de Sequência de RNA
20.
Clin Proteomics ; 16: 2, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30675135

RESUMO

Background: The biomarkers alpha-fetoprotein (AFP) and protein induced by vitamin K absence/antagonist-II (PIVKA-II) may be useful for detecting early-stage hepatocellular carcinoma (HCC). We evaluated the performance of AFP and PIVKA-II levels, alone and in combination with clinical factors, for the early detection of HCC. Methods: In a case-control study, serum AFP and PIVKA-II were measured using the ARCHITECT immunoassay analyzer system in a cohort of 119 patients with HCC, 215 patients with non-malignant liver disease, and 34 healthy subjects. Five predictive models for detecting HCC were developed based on age, gender, AFP, and/or PIVKA-II levels; the best model was validated in an independent cohort of 416 patients with HCC and 412 control subjects with cirrhosis. Results: In both cohorts, AFP and PIVKA-II concentrations were higher in patients with HCC compared to healthy controls and patients with non-malignant liver disease. The model that combined AFP and PIVKA-II, age, and gender had the highest AUC of 0.95 (0.95, 95% CI 0.93-0.98), with a sensitivity of 93% and a specificity of 84% in the development cohort, and an AUC of 0.87 (95% CI 0.85-0.90), sensitivity of 74%, and specificity of 85% in the validation cohort. When limiting the validation cohort to only early-stage HCC, the AUC was 0.85 (95% CI 0.81-0.88), sensitivity was 70%, and specificity was 86%. Conclusions: Compared to each biomarker alone, the combination of AFP and PIVKA-II with age and gender improved the accuracy of detecting HCC and differentiating HCC from non-malignant liver disease.

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