Multivariate Index Assay Research Articles

Combining A Second-Generation Multivariate Index Assay with Ovarian Imaging Improves the Preoperative Assessment of An Adnexal Mass

Background: To understand the relationship between imaging and the next generation multivariate index assay (MIA2G) in the preoperative assessment of an adnexal mass. Methods: Serum samples and imaging data from two previously published studies are reanalyzed using the MIA2G test. We calculated the clinical performance of MIA2G and discrete imaging features associated with malignant risk. Results: 878 women were eligible for this analysis, 48.3% post-menopausal and 51.7% pre-menopausal. The prevalence of having a malignant pathology was 18%. Ultrasound was the most frequently used imaging modality. The combination of MIA2G “or” ultrasound resulted in higher sensitivity than either test alone, 93.5% compared to 87.6% for MIA2G and 74.2% for ultrasound. The negative predictive value was high: 94.6% for ultrasound, 98.1% for MIA2G “or” ultrasound. MIA2G “and” ultrasound had higher specificity but lower sensitivity than MIA2G or ultrasound alone. Similar results were seen for CT scan when evaluated with MIA2G. Conclusion: MIA2G and pelvic imaging are complementary tests and interpreting them together can provide important information about the malignant risk of an ovarian tumor. For physicians making decisions about a referral to a specialist, the combination of MIA2G “or” ultrasound has the highest sensitivity in predicting ovarian malignancy.

Ethnic disparity in clinical performance between multivariate index assay and CA125 in detection of ovarian malignancy.

Aim: Based on evidence that African-American (AA) women have lower CA125 values than Caucasian (C) women, we investigated this to see if this disparity would have an impact on ovarian cancer detection using CA125 and multivariate index assay (MIA). Materials & methods: Serum from two prospective trials of 1029 (274 malignancies [250 C/24AA]) were analyzed for CA125 and MIA results. Clinical performance was calculated. Results: Sensitivity of MIA in Caucasian women was 93.2%, 74.4% for CA125 at the ACOG approved cut-off level of 200 U/ml cutoff, and 80.4% using the 2007, Dearking 67 U/ml cutoff. In AA American women, MIA sensitivity was 79.2%, 33.3% for CA125 at the ACOG approved cut-off levels and 62.5% at the 2007, Dearking 67 U/ml cutoff. Conclusion: Our results support that CA125 in AA women with adnexal masses has lower sensitivity than MIA no matter what the cutoff value is. Implementation of MIA in evaluation of adnexal masses should increase sensitivity of detection of malignancy compared with CA125, particularly in AA women.

Clinical Performance Comparison of Two In-Vitro Diagnostic Multivariate Index Assays (IVDMIAs) for Presurgical Assessment for Ovarian Cancer Risk.

IntroductionAdnexal or pelvic mass is a finding that commonly raises suspicion for malignancy, especially for ovarian cancer. Proper identification prior to surgery would permit appropriate referral to a specialty center in cases likely to be ovarian cancer, as optimal outcomes in such cases are obtained when surgical staging and treatment are provided at the time of initial surgery.MethodsWe compared the screening capabilities of two in vitro diagnostic multivariate index assays (IVDMIAs), a new IVDMIA (second-generation multivariate index assay: MIA2G) and a currently used triage algorithm (Risk of Ovarian Malignancy Assay: ROMA).ResultsAmong 245 subjects (24.7%) determined to have a malignancy, ROMA misclassified 51 malignancies (including 10 high-grade ovarian malignancies), whereas MIA2G misclassified 22 (including 5 high-grade ovarian malignancies). Early stage cancers were more frequently misclassified by ROMA (20 vs. 8 cases). The rate of “test-negative” malignancies was significantly higher for ROMA, while the rate of “test-positive” benign cases was significantly higher for MIA2G.ConclusionTriage algorithms play an important role in improving clinical outcomes for women presenting with an adnexal mass regardless of the eventual diagnosis. In this study, MIA2G was shown to correctly predict more cases of ovarian cancer than the ROMA algorithm.FundingAspira Labs/Vermillion Inc.Electronic supplementary materialThe online version of this article (10.1007/s12325-019-01010-8) contains supplementary material, which is available to authorized users.

Abstract 3339: Ethnic disparity in ovarian malignancy tumor markers: MIA and ROMA

Abstract Objective: Review and analyze serum values of Risk of Ovarian Malignancy Algorithm (ROMA) and Multivariate Index Assay (MIA) in subgroups of women who underwent surgery for adnexal masses to determine sensitivity in different ethnic populations. Methods: Serum samples from 179 women diagnosed with ovarian malignancy were analyzed for ROMA and MIA results. Biomarker data was obtained from previous prospective studies that validated the MIA test. Of these, 167 women were Caucasian (C) and 12 African-American (AA) in the MIA testing. Sample for ROMA included 161 C and 11 AA. Sensitivity (true positive rate) for preoperative test results were calculated using DTCompair package of the R programming language. In premenopausal women, a risk of ovarian malignancy algorithm (ROMA) value equal to or greater than 1.14 indicates a high risk of finding epithelial ovarian cancer. In premenopausal women, MIA values of greater than 5.0 are associated with greater risk of malignancy. In postmenopausal women, a ROMA value equal to or greater than 2.99 indicates a high risk of finding epithelial ovarian cancer. In postmenopausal women, MIA values of greater than 4.4 are associated with greater risk of malignancy. Results: Primary ovarian malignancy was diagnosed in 179 cases (167 C/12 AA). Sensitivity testing results are seen for each subgroup and for MIA levels and CA125 results: Primary Ovarian Malignancy: Caucasian MIA 97.0%, ROMA 89.4%, AA MIA 75.0% ROMA 45.5%. Sensitivity of ROMA in AA premenopausal women was 50% and in postmenopausal women 33.3 %. Conclusion: Our results demonstrate that ROMA in both C andAA women with adnexal masses have lower sensitivity for detection of malignancy than does MIA. It is more pronounced in AA women. Implementation of MIA in evaluation of adnexal masses will increase sensitivity of detection of malignancy compared to CA125 testing, with most marked results in AA women. Key Words: Ethnicity, CA125, and Multivariate Index Assay Sensitivity of MIA vs. ROMA Ovarian MalignancyRaceTestStatusMenopauseNumberSensitivityCaucasianMIAAll16797.0CaucasianMIAPre4395.3CaucasianMIAPost12497.6CaucasianROMAAll16189.4CaucasianROMAPre4092.5CaucasianROMAPost12188.4African AmericaMIAAll1275African AmericaMIAPre977.8African AmericaMIAPost366.7African AmericaROMAAll1145.5African AmericaROMAPre850.0African AmericaROMAPost333.3 Citation Format: Charles Dunton, Herbert Fritsche, Rowan Bullock. Ethnic disparity in ovarian malignancy tumor markers: MIA and ROMA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3339.

Multivariate Index Assay Is Superior to CA125 and HE4 Testing in Detection of Ovarian Malignancy in African-American Women.

Objective:To review and analyze the serum values of risk of ovarian malignancy algorithm (ROMA) and multivariate index assay (MIA) in subgroups of women who underwent surgery for adnexal masses to determine sensitivity, specificity, and positive and negative predictive values for the detection of malignancy in different ethnic populations.Methods:Serum samples from 2 prospective trials of 1029 women in which 274 women diagnosed with malignancy were analyzed for ROMA scores and MIA results. Biomarker data were obtained from the previous prospective studies that validated the MIA test. Of these, 250 women were Caucasian (C) and 24 were African-American (AA). Sensitivity, specificity, positive and negative predictive values, and confidence intervals for preoperative test results were calculated using DTComPair package of the R programming language. In premenopausal women, a ROMA value equal to or greater than 1.14 indicates a high risk of finding epithelial ovarian cancer. In premenopausal women, MIA values greater than 5.0 are associated with a greater risk of malignancy. In postmenopausal women, a ROMA value equal to or greater than 2.99 indicates a high risk of finding epithelial ovarian cancer. In postmenopausal women, MIA values greater than 4.4 are associated with a greater risk of malignancy.Results:Primary ovarian malignancy was diagnosed in 179 cases (167 C/12 AA) and metastatic disease to the ovary in an additional 27 cases (22 C/5 AA). Overall results are shown below.Conclusions:Our results demonstrate that ROMA in AA women with adnexal masses have lower sensitivity for the detection of malignancy than does MIA. Implementation of MIA in the evaluation of adnexal masses will increase the sensitivity of the detection of malignancy compared with ROMA, with the most marked results in AA women.

Analytical Validation of qPCR-Based Multivariate Index Assays in a Clinical Laboratory: Practical Challenges and Limitations.

Multivariate index assays (MIAs) to evaluate disease status and/or therapeutic efficacy are increasingly being used in clinical laboratories as laboratory-developed tests (LDTs). Before clinical use, diagnostic and analytical performance specifications of LDTs must be established. Several regulatory guidelines have been published that address specific components of validation procedures, but the interpretation for the analytical validation of MIAs is ambiguous and creates confusion when implementing a novel MIA in the clinical laboratory. CLSI guidelines and published methods were evaluated to develop a validation strategy to establish analytical sensitivity, precision, specificity, and stability for qPCR-based MIAs. Limitations and challenges identified while evaluating guidelines and literature and implementing this strategy are discussed in this review, including sample sourcing and integrity, laboratory contamination, and sample throughput. Due to the diversity of qPCR-based MIAs, we discuss additional considerations for researchers intending to transfer MIAs to a clinical laboratory. A practical strategy to assess the analytical performance characteristics for validation of qPCR-based MIAs was developed and tested before diagnostic clinical use. Several important limitations, challenges, and considerations were identified during development of the analytical validation procedures that are not addressed in regulatory guidelines or published literature. The described strategy can provide insight for future developers of MIAs and clinical laboratories implementing MIAs as LDTs.

High "phi"ve.

To the Editor: The Beckman Coulter Prostate Health Index ( phi )1 is an in vitro diagnostic multivariate index assay incorporating immunoassay measurements of prostate-specific antigen (PSA), free PSA, and the free PSA isoform [−2]proPSA (p2PSA) in serum and is calculated as (p2PSA /free PSA × √PSA). In 2012, phi was approved by the Food and Drug Administration to aid in the detection of prostate cancer in men ≥50 years with total PSA concentrations from 4 to 10 ng/mL with a nonsuspicious digital rectal examination. Phi has also been used to detect prostate cancer in the 2–10 ng/mL PSA …

Preoperative assessment of ovarian tumors using a modified multivariate index assay

BackgroundPreoperative differentiation between benign and malignant masses can be challenging. The aim of this research was to evaluate the performance of a modified multivariate index assay (MIA) in detecting ovarian cancer and to compare the effectiveness of gynecologist assessment, cancer antigen (CA) 125, and MIA for identifying ovarian masses with high suspicion of malignancy.ResultsThis prospective observational study included 150 women with ovarian masses who underwent surgery in the Maternity Teaching Hospital from December 2014 to May 2016. Preoperative estimation of modified MIA, assessment by a gynecologist, and CA 125 level correlated with the surgical histopathology. A modified MIA was implemented because of lack of access to the software typically used. Among 150 enrolled women there were 30 cases of malignancy, including 8 cases (26%) of early-stage ovarian cancer and 22 cases (74%) of late-stage cancer. MIA showed high specificity (96.7%) in detecting cancer and a sensitivity of 70%, with a positive predictive value of 84% and a negative predictive value of 92.8%. No significant differences were detected between the MIA results and the histopathology results (P = 0.267). For early-stage ovarian cancer, the sensitivity of MIA was 100% compared with 75% for CA 125 alone.ConclusionMIA seems to be effective for evaluation of ovarian tumors with higher specificity and positive predictive value than CA 125 while maintaining high negative predictive value and with only a slightly lower overall sensitivity. For evaluation of early-stage ovarian cancer, MIA showed a much higher sensitivity that markedly outperformed CA 125 alone. This modified MIA strategy may be particularly useful in low resource setting.

Circulating biomarkers in epithelial ovarian cancer diagnosis: from present to future perspective.

Ovarian cancer (OC) represents the most lethal gynecological cancer and the poor prognosis is often attributable to late diagnosis. The diagnostic approach to woman presenting with pelvic mass is difficult and differential diagnosis often requires invasive histological examination. Serum CA125 and HE4, as well as the most of the other serum biomarkers discovered and validated, are not sufficiently sensitive and specific to make early diagnosis. Moreover, conflicting results exist about the improvement of diagnostic performance by using multivariate index assays, developed by combining circulating biomarkers with other variables (i.e., ultrasound and/or menopausal status and/or age), in comparison to CA125 or HE4 alone. In the last years, several studies focused on the microRNAs (miRs), short single-stranded non-coding RNA that regulate several messenger RNAs (mRNAs). As in other cancer types, the aberrant miRs expression has been demonstrated in gynecological cancers, in both tissues and serum samples. In particular, the diagnostic performance of single or miRs panels resulted very high. However, to date, despite the potential clinical utility has been demonstrated, none of these miRs has been validated in large OC populations.

A Perspective on Ovarian Cancer Biomarkers: Past, Present and Yet-To-Come.

The history of biomarkers and ultrasonography dates back over more than 50 years. The present status of biomarkers used in the context of ovarian cancer is addressed. Attention is given to new interpretations of the etiology of ovarian cancer. Cancer antigen 125 (CA125) and multivariate index assays (Ova1, Risk of Ovarian Malignancy Algorithm, Overa) are biomarker-driven considerations that are presented. Integration of biomarkers into ovarian cancer diagnostics and screening are presented in conjunction with ultrasound. Consideration is given to the serial application of both biomarkers and ultrasound, as well as morphology-based indices. Attempts are made to foresee how individualized molecular signatures may be able to both provide an alert of the potential for ovarian cancer and to provide molecular treatments tailored to a personalized genetic signature. In the future, an annual pelvic ultrasound and a comprehensive serum biomarker screening/diagnostic panel may replace the much maligned bimanual examination as part of the annual gynecologic examination. Taken together, it is likely that a new medical specialty for screening and early diagnostics will emerge for physicians and epidemiologists, a field of study that is independent of patient gender, organ, or the subspecialties of today.

The analytical validation of the Oncotype DX Recurrence Score assay.

In vitro diagnostic multivariate index assays are highly complex molecular assays that can provide clinically actionable information regarding the underlying tumour biology and facilitate personalised treatment. These assays are only useful in clinical practice if all of the following are established: analytical validation (i.e., how accurately/reliably the assay measures the molecular characteristics), clinical validation (i.e., how consistently/accurately the test detects/predicts the outcomes of interest), and clinical utility (i.e., how likely the test is to significantly improve patient outcomes). In considering the use of these assays, clinicians often focus primarily on the clinical validity/utility; however, the analytical validity of an assay (e.g., its accuracy, reproducibility, and standardisation) should also be evaluated and carefully considered. This review focuses on the rigorous analytical validation and performance of the Oncotype DX® Breast Cancer Assay, which is performed at the Central Clinical Reference Laboratory of Genomic Health, Inc. The assay process includes tumour tissue enrichment (if needed), RNA extraction, gene expression quantitation (using a gene panel consisting of 16 cancer genes plus 5 reference genes and quantitative real-time RT-PCR), and an automated computer algorithm to produce a Recurrence Score® result (scale: 0–100). This review presents evidence showing that the Recurrence Score result reported for each patient falls within a tight clinically relevant confidence interval. Specifically, the review discusses how the development of the assay was designed to optimise assay performance, presents data supporting its analytical validity, and describes the quality control and assurance programmes that ensure optimal test performance over time.

Application of cancer-associated glycoforms and glycan-binding probes to an in vitro diagnostic multivariate index assay for precise diagnoses of cancer.

Personalized medicine has emerged as a widely accepted trend in medicine for the efficacious and safe treatment of various diseases. It covers every medical treatment tailored according to various properties of individuals. Cancer‐associated glycosylation mirrors cancer states more precisely, and this “sweet side of cancer” is thus intended to spur the development of an advanced in vitro diagnostic system. The changes of glyco‐codes are often subtle and thus not easy to trace, thereby making it difficult to discriminate changes from various compounding factors. Special glycan‐binding probes, often lectins, can be paired with aglycosylated antibodies to enable quantitative and qualitative measurements of glycoforms. With the in vitro diagnosis multivariate index assay (IVDMIA) considered to be capable of yielding patient‐specific results, the combinatorial use of multiple glycoproteins may be a good modality to ensure disease‐specific, personalized diagnoses.

Validation of a second-generation multivariate index assay for malignancy risk of adnexal masses

Women with adnexal mass suspected of ovarian malignancy are likely to benefit from consultation with a gynecologic oncologist, but imaging and biomarker tools to ensure this referral show low sensitivity and may miss cancer at critical stages. The multivariate index assay (MIA) was designed to improve the detection of ovarian cancer among women undergoing surgery for a pelvic mass. To improve the prediction of benign masses, we undertook the redesign and validation of a second-generation MIA (MIA2G). MIA2G was developed using banked serum samples from a previously published prospective, multisite registry of patients who underwent surgery to remove an adnexal mass. Clinical validity was then established using banked serum samples from the OVA500 trial, a second prospective cohort of adnexal surgery patients. Based on the final pathology results of the OVA500 trial, this intended-use population for MIA2G testing was high risk, with an observed cancer prevalence of 18.7% (92/493). Coded samples were assayed for MIA2G biomarkers by an external clinical laboratory. Then MIA2G results were calculated and submitted to a clinical statistics contract organization for decoding and comparison to MIA results for each subject. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated, among other measures, and stratified by menopausal status, stage, and histologic subtype. Three MIA markers (cancer antigen 125, transferrin, and apolipoprotein A-1) and 2 new biomarkers (follicle-stimulating hormone and human epididymis protein 4) were included in MIA2G. A single cut-off separated high and low risk of malignancy regardless of patient menopausal status, eliminating potential for confusion or error. MIA2G specificity (69%, 277/401 [n/N]; 95% confidence interval [CI], 64.4-73.4%) and PPV (40%, 84/208; 95% CI, 33.9-47.2%) were significantly improved over MIA (specificity, 54%, 215/401; 95% CI, 48.7-58.4%, and PPV, 31%, 85/271; 95% CI, 26.1-37.1%, respectively) in this cohort. Sensitivity and NPV were not significantly different between the 2 tests. When combined with physician assessment, MIA2G correctly identified 75% of the malignancies missed by physician assessment alone. MIA2G specificity and PPV were significantly improved compared with MIA, while sensitivity and NPV were unchanged. The second-generation test significantly improved the predicted efficiency of triage vs MIA without sacrificing high sensitivity and NPV, which are essential for effectiveness.

Cardiac ScoreCard: A diagnostic multivariate index assay system for predicting a spectrum of cardiovascular disease

Clinical decision support systems (CDSSs) have the potential to save lives and reduce unnecessary costs through early detection and frequent monitoring of both traditional risk factors and novel biomarkers for cardiovascular disease (CVD). However, the widespread adoption of CDSSs for the identification of heart diseases has been limited, likely due to the poor interpretability of clinically relevant results and the lack of seamless integration between measurements and disease predictions. In this paper we present the Cardiac ScoreCard—a multivariate index assay system with the potential to assist in the diagnosis and prognosis of a spectrum of CVD. The Cardiac ScoreCard system is based on lasso logistic regression techniques which utilize both patient demographics and novel biomarker data for the prediction of heart failure (HF) and cardiac wellness. Lasso logistic regression models were trained on a merged clinical dataset comprising 579 patients with 6 traditional risk factors and 14 biomarker measurements. The prediction performance of the Cardiac ScoreCard was assessed with 5-fold cross-validation and compared with reference methods. The experimental results reveal that the ScoreCard models improved performance in discriminating disease versus non-case (AUC=0.8403 and 0.9412 for cardiac wellness and HF, respectively), and the models exhibit good calibration. Clinical insights to the prediction of HF and cardiac wellness are provided in the form of logistic regression coefficients which suggest that augmenting the traditional risk factors with a multimarker panel spanning a diverse cardiovascular pathophysiology provides improved performance over reference methods. Additionally, a framework is provided for seamless integration with biomarker measurements from point-of-care medical microdevices, and a lasso-based feature selection process is described for the down-selection of biomarkers in multimarker panels.

Cost-effectiveness analysis of a multivariate index assay compared to modified American College of Obstetricians and Gynecologists criteria and CA-125 in the triage of women with adnexal masses

Objective:To evaluate the cost-effectiveness of the multivariate index assay (MIA) for use in triaging women with an adnexal mass relative to modified American College of Obstetricians and Gynecologists (mACOG) referral guidelines and CA-125 testing alone.Methods:The MIA triage algorithm was based on qualitative serum testing of five biomarkers: transthyretin, apolipoprotein, A-1, 2-microglobulin, transferrin, and CA-125. An economic analysis was developed to evaluate the clinical and cost implications of adopting MIA in clinical practice versus the mACOG referral guidelines and CA-125 alone, over a lifetime horizon, from the perspective of the public payer. Clinical parameters used to characterize patients’ disease status, quality of life, and treatment decisions were estimated using the results of published studies; costs were approximated using reimbursement rates from CMS fee schedules. Model endpoints included overall survival (OS), costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). The cost-effectiveness threshold was set to $50,000 per QALY. One-way sensitivity analysis was performed to assess uncertainty of individual parameters included in the analysis. All costs were reported in 2014 US dollars.Results:Use of MIA was cost-effective, resulting in fewer re-operations and pre-treatment CT scans. Overall MIA resulted in an ICER of $35,094/QALY gained. MIA was also cost-saving and QALY-increasing compared to use of CA-125 alone with an ICER of $12,189/QALY gained. One-way sensitivity analysis showed the ICER was most affected by the following parameters: (1) sensitivity of MIA; (2) sensitivity of mACOG; and (3) percentage of patients, not referred to a gynecologic oncologist, who were correctly diagnosed with advanced epithelial ovarian cancer (EOC).Conclusion:Use of MIA is a more cost-effective triage strategy than mACOG or CA-125. It is expected to increase the percentage of women with ovarian cancer that are referred to gynecologic oncologists, which is shown to improve clinical outcomes. Limitations include the use of assumptions when published data was unavailable, and the use of multiple sources for survival data.

Derivation of a second generation multivariate index assay to improve specificity in pre-surgical evaluation of adnexal masses for risk of ovarian malignancy.

5561 Background: The FDA cleared in vitro diagnostic multivariate index assay OVA1, with its intended utility to assist in referral of high risk patients to gynecologic oncologists, was by design t...

Validation of a second-generation mia (MIA2G) for triage of adnexal masses.

5556 Background: Many women with ovarian cancer receive non-guideline care. Failure to refer to a gynecologic oncologist is one likely cause. To improve specificity of Multivariate Index Assay (MIA...

Semi-quantitative Measurement of a Specific Glycoform Using a DNA-tagged Antibody and Lectin Affinity Chromatography for Glyco-biomarker Development *

Aberrant glycosylation-targeted disease biomarker development is based on cumulative evidence that certain glycoforms are mass-produced in a disease-specific manner. However, the development process has been hampered by the absence of an efficient validation method based on a sensitive and multiplexed platform. In particular, ELISA-based analytical tools are not adequate for this purpose, mainly because of the presence of a pair of N-glycans of IgG-type antibodies. To overcome the associated hurdles in this study, antibodies were tagged with oligonucleotides with T7 promoter and then allowed to form a complex with corresponding antigens. An antibody-bound specific glycoform was isolated by lectin chromatography and quantitatively measured on a DNA microarray chip following production of fluorescent RNA by T7-trascription. This tool ensured measurement of targeted glycoforms of multiple biomarkers with high sensitivity and multiplexity. This analytical method was applied to an in vitro diagnostic multivariate index assay where a panel of hepatocellular carcinoma (HCC) biomarkers comprising alpha-fetoprotein, hemopexin, and alpha-2-macroglobulin (A2M) was examined in terms of the serum level and their fuco-fractions. The results indicated that the tests using the multiplexed fuco-biomarkers provided improved discriminatory power between non- hepatocellular carcinoma and hepatocellular carcinoma subjects compared with the alpha-fetoprotein level or fuco-alpha-fetoprotein test alone. The developed method is expected to facilitate the validation of disease-specific glycan biomarker candidates.

Feasibility of detecting prostate cancer by ultraperformance liquid chromatography-mass spectrometry serum metabolomics.

Prostate cancer (PCa) is the second leading cause of cancer-related mortality in men. The prevalent diagnosis method is based on the serum prostate-specific antigen (PSA) screening test, which suffers from low specificity, overdiagnosis, and overtreatment. In this work, untargeted metabolomic profiling of age-matched serum samples from prostate cancer patients and healthy individuals was performed using ultraperformance liquid chromatography coupled to high-resolution tandem mass spectrometry (UPLC-MS/MS) and machine learning methods. A metabolite-based in vitro diagnostic multivariate index assay (IVDMIA) was developed to predict the presence of PCa in serum samples with high classification sensitivity, specificity, and accuracy. A panel of 40 metabolic spectral features was found to be differential with 92.1% sensitivity, 94.3% specificity, and 93.0% accuracy. The performance of the IVDMIA was higher than the prevalent PSA test. Within the discriminant panel, 31 metabolites were identified by MS and MS/MS, with 10 further confirmed chromatographically by standards. Numerous discriminant metabolites were mapped in the steroid hormone biosynthesis pathway. The identification of fatty acids, amino acids, lysophospholipids, and bile acids provided further insights into the metabolic alterations associated with the disease. With additional work, the results presented here show great potential toward implementation in clinical settings.

The effect of ovarian imaging on the clinical interpretation of a multivariate index assay

The purpose of this study was to investigate the relationship between imaging and the multivariate index assay (MIA) in the prediction of the likelihood of ovarian malignancy before surgery. Subjects were recruited in 2 related prospective, multiinstitutional trials that involved 44 sites across the United States. Women had ovarian imaging, biomarker analysis, and surgery for an adnexal mass. Ovarian tumors were classified as high risk for solid or papillary morphologic condition on imaging study. Biomarker and imaging results were correlated with surgical findings. Of the 1110 women who were enrolled with an adnexal mass on imaging, 1024 cases were evaluable. There were 255 malignant and 769 benign tumors. High-risk findings were present in 46% of 1232 imaging tests and 61% of 1024 MIA tests. The risk of malignancy increased with rising MIA scores; similarly, the likelihood of malignancy was higher for high-risk, compared with low-risk, imaging. Sensitivity and specificity for the prediction of malignancy were 98% (95% CI, 92-99) and 31% (95% CI, 27-34) for ultrasound or MIA; 68% (95% CI, 58-77) and 75% (95% CI, 72-78) for ultrasound and MIA, respectively. For computed tomography scan or MIA, sensitivity was 97% (95% CI, 92-99) and specificity was 22% (95% CI, 16-28); the sensitivity and specificity for computed tomography scan and MIA were 71% (95% CI, 62-79) and 70% (95% CI, 63-76). Only 1.6% of ovarian tumors were malignant when both tests indicated low risk. A logistic regression model to predict risk of malignancy is presented. An understanding of how pelvic imaging influences the MIA score can help clinicians better interpret the malignant risk of an ovarian tumor.