RCTUEA is intended to aid in assessing whether a premenopausal woman who presents with an ovarian adnexal mass is at high or low likelihood of finding malignancy on surgery. RCTUEA is indicated for women who meet the following criteria: over age 18; ovarian adnexal mass present for which surgery is planned, and not yet referred to an oncologist. RCTUEA must be interpreted in conjunction with an independent clinical and radiological assessment. The test is not intended as a screening or stand-alone diagnostic assay.

The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassay analyzers.

PRECAUTION: RCTUEA should not be used without an independent clinical/ radiological evaluation and is NOT intended to be a screening test or to determine whether a patient should proceed to surgery. Incorrect use of RCTUEA carries the risk of unnecessary testing, surgery and/or delayed diagnosis.

Device Description

ROMA Calculation Tool Using Elecsys Assays (RCTUEA) is a qualitative test for serum and plasma (K2-EDTA, K3-EDTA and Li-Heparin) that combines the results of the Elecsys HE4 assay, Elecsys CA 125 II assay and menopausal status into a numerical score. ROMA was developed using separate logistic regression equations for premenopausal and postmenopausal women:

Pre menopausal:

Predictive Index (PI) = - 12.0 + 2.38 x LN[HE4] + 0.0626 x LN[CA 125] Post menopausal:

Predictive Index (PI) = - 8.09 + 1.04 x LN[HE4] + 0.732 x LN[CA 125] RCTUEA value = exp (PI) / [1 + exp(PI)b)] x 10

RCTUEA is used to stratify women into likelihood groups for finding cancer on surgery. In order to provide a specificity level of 75 %, a cutoff point of ≥ 1.14 was used for premenopausal women and ≥ 2.99 was used for postmenopausal women who present with an ovarian adnexal mass. Women with RCTUEA results above these cutoff points are at high likelihood of finding malignancy on surgery.

The immunoassays used in RCTUEA are:

Elecsys HE4: an electrochemiluminescence immunoassay for the quantitative determination of HE4 in human serum and plasma

Elecsys CA 125 II: an electrochemiluminescence immunoassay for the quantitative determination of OC 125 reactive determinants in human serum and plasma.

AI/ML Overview

Here's a breakdown of the acceptance criteria and study information for the ROMA Calculation Tool Using Elecsys Assays (RCTUEA), based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implied by the performance goals for sensitivity, specificity, and predictive values. The study reports these values for different cohorts. The primary focus for the device's utility is its ability to stratify women into high or low likelihood groups for finding malignancy on surgery, especially its adjunctive use with Initial Cancer Risk Assessment (ICRA).

Metric	Premenopausal (EOC Only) (Target/Achieved)	Postmenopausal (EOC Only) (Target/Achieved)	All Cancers & LMP Tumors (Adjunctive Use) (Target/Achieved)	Notes
Sensitivity	100% (9/9) (66.4% - 100% CI)	89.5% (34/38) (75.2% - 97.1% CI)	Increased from 76.9% to 90.8% (81.0% - 96.5% CI)	The document states RTCUEA was used to "aid in assessing whether a premenopausal woman...is at high or low likelihood of finding malignancy... In order to provide a specificity level of 75%". This implicitly sets the specificity as the primary acceptance criterion, with other metrics assessed relative to this. For standalone RCTUEA, the specificity was targeted at 75%. For adjunctive use, the goal appeared to be demonstrating a statistically significant increase in NPV and an increase in sensitivity, even if accompanied by a decrease in specificity and PPV. The significant increase in NPV (P=0.0000) for adjunctive use is a key finding supporting its effectiveness in ruling out cancer.
Specificity	77.6% (177/228) (71.7% - 82.9% CI)	82.5% (118/143) (75.3% - 88.4% CI)	Decreased from 84.4% to 70.4% (65.4% - 75.0% CI)
Positive Predictive Value (PPV)	15.0% (9/60) (7.1% - 26.6% CI)	57.6% (34/59) (44.1% - 70.4% CI)	Decreased from 46.3% to 34.9% (27.8% - 42.6% CI)
Negative Predictive Value (NPV)	100.0% (177/177) (97.9% - 100% CI)	96.7% (118/122) (91.8% - 99.1% CI)	Increased from 95.4% to 97.8% (95.2% - 99.2% CI)
TP-FP	77.6% (72.1% - 83.2% CI)	72.0% (60.2% - 83.8% CI)	61.1% (52.5% - 69.7% CI)

2. Sample Size and Data Provenance

Test Set Sample Size:
- Total Evaluated: 455 women
- Premenopausal (Primary EOC analysis): 237
- Postmenopausal (Primary EOC analysis): 181
- Adjunctive Use Analysis: 436 (65 Malignant, 371 No Malignancy by Pathology)
Data Provenance: Prospective, multi-center clinical trial. The document does not specify the countries of origin for the data, but it mentions samples were tested at "three US testing sites," which implies at least some data is from the US. The "multi-center" nature suggests other locations as well, but these are not named.

3. Number of Experts and Qualifications for Ground Truth

The document does not specify the number of experts used to establish the ground truth for the test set.
Qualifications of Experts: The ground truth was based on "histopathology reports collected after surgery." This implies pathologists are the experts, but their specific qualifications (e.g., years of experience, board certification) are not provided. An "Initial Cancer Risk Assessment (ICRA)" was completed by a "nurse practitioner, physician assistant or a non-gynecological oncologist," but this was a baseline assessment, not the definitive ground truth.

4. Adjudication Method for the Test Set

The document does not describe a specific adjudication method (e.g., 2+1, 3+1, none) for resolving discrepancies in the ground truth. It simply states that "histopathology reports were collected after surgery," implying the single report served as the definitive ground truth.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

The document describes a study comparing the performance of the RCTUEA alone versus the performance of an Initial Cancer Risk Assessment (ICRA) alone, and then versus the adjunctive use of RCTUEA with ICRA.
Effect Size of Human Improvement with AI vs. without AI assistance:
- This is not a traditional MRMC study where human readers interpret cases with and without AI assistance to measure reader improvement. Instead, it compares a clinical assessment (ICRA, performed by clinicians) to the device's output, and then the combination.
- For "all malignancies including EOC, non-epithelial ovarian cancer, other gynecologic and non-gynecologic cancers," when RCTUEA was used adjunctively with ICRA:
  - Sensitivity increased from 76.9% (ICRA alone) to 90.8% (ICRA + RCTUEA). This represents an increase of 13.9 percentage points.
  - Specificity decreased from 84.4% (ICRA alone) to 70.4% (ICRA + RCTUEA). This represents a decrease of 14 percentage points.
  - NPV increased from 95.4% (ICRA alone) to 97.8% (ICRA + RCTUEA), which was statistically significant (P=0.0000). This indicates an improvement in the ability to rule out cancer.

6. Standalone Performance Study (Algorithm Only)

Yes, a standalone performance study was done. The performance metrics for RCTUEA alone (without ICRA) are reported for both premenopausal and postmenopausal women with Epithelial Ovarian Cancer (EOC) only.
- Premenopausal (EOC): Sensitivity 100%, Specificity 77.6%
- Postmenopausal (EOC): Sensitivity 89.5%, Specificity 82.5%
Performance of RCTUEA for "all malignancies and LMP tumors" is also shown:
- Sensitivity: 86.2%
- Specificity: 79.5%

7. Type of Ground Truth Used

Pathology: The primary and definitive ground truth used was "histopathology reports collected after surgery."

8. Sample Size for the Training Set

The document does not explicitly state the sample size used for the training set. It describes the RCTUEA calculation (logistic regression equations) as "developed using separate logistic regression equations," but does not provide details about the data used for this development phase. The reported clinical trial is for effectiveness determination (a test set).

9. How the Ground Truth for the Training Set Was Established

The document states that the ROMA algorithm was "developed using separate logistic regression equations." However, it does not provide information on how the ground truth for the training data used to develop these equations was established. It is reasonable to assume it would also have been based on histopathology, but this is not explicitly stated for the training phase.

Summary

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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

June 15, 2016

Roche Diagnostics Mr. Angelo Pereira Regulatory Affairs Program Manager 9115 Hague Road Indianapolis, IN 46250

Re: K153607

Trade/Device Name: Roma Calculation Tool Using Elecsys Assays Regulation Number: 21 CFR 866.6050 Regulation Name: Ovarian adnexal mass assessment score test system Regulatory Class: II Product Code: ONX Dated: May 13, 2016 Received: May 17, 2016

Dear Mr. Pereira:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food. Drug. and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21. Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm. Also, please note the regulation entitled. "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to

http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely yours.

Kelly Oliner -S

For.

Leonthena R. Carrington, MS, MBA, MT(ASCP) Director Division of Immunology and Hematology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K153607

Device Name ROMA Calculation Tool Using Elecsys Assays

Indications for Use (Describe)

The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassay analyzers.

Type of Use (Select one or both, as applicable)
	☒ Prescription Use (Part 21 CFR 801 Subpart D)
	☐ Over-The-Counter Use (21 CFR 801 Subpart C)

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510(k) Summary

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This 510(k) summary of safety and effectiveness is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92

	Address	Roche Diagnostics9115 Hague RdIndianapolis, IN 46250
SubmitterInformation	Contact Person	Angelo Pereiraangelo.pereira@roche.com
	Date prepared	June 06, 2016

Device Name	Proprietary names:	ROMA Calculation Tool Using Elecsys Assays
	Common names:	ROMA (Risk of Ovarian Malignancy Algorithm)
	Product Code:	ONX
	Predicate Device:	Fujirebio ROMA (K103358)

EstablishmentRegistration	For the ROMA Calculation Tool Using Elecsys Assays (RCTUEA), theElecsys HE4 assay and the Elecsys CA 125 II assay the establishmentregistration numbers for Roche Diagnostics GmbH sites in Mannheim,Germany and Penzberg, Germany are 9610126 and 9610529,respectively. The establishment registration number for RocheDiagnostics, Indianapolis, USA is 1823260
-------------------------------	---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

Classification The FDA has classified the Ovarian Adnexal Mass Assessment Score . Test as a Class II device.

Panel	ProductCode	Classification Name	RegulationCitation
Immunology	ONX	Ovarian Adnexal Mass AssessmentScore Test System	21 CFR 862.6050

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Device ROMA Calculation Tool Using Elecsys Assays (RCTUEA) is a qualitative Description test for serum and plasma (K2-EDTA, K3-EDTA and Li-Heparin) that combines the results of the Elecsys HE4 assay, Elecsys CA 125 II assay and menopausal status into a numerical score. ROMA was developed using separate logistic regression equations for premenopausal and postmenopausal women:

Pre menopausal:

Predictive Index (PI) = - 12.0 + 2.38 x LN[HE4] + 0.0626 x LN[CA 125] Post menopausal:

Predictive Index (PI) = - 8.09 + 1.04 x LN[HE4] + 0.732 x LN[CA 125] RCTUEA value = exp (PI) / [1 + exp(PI)b)] x 10

The immunoassays used in RCTUEA are:

Elecsys HE4: an electrochemiluminescence immunoassay for the quantitative determination of HE4 in human serum and plasma

Elecsys CA 125 II: an electrochemiluminescence immunoassay for the quantitative determination of OC 125 reactive determinants in human serum and plasma.

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IntendedUse/Indicationsfor Use	ROMA Calculation Tool Using Elecsys Assays (RCTUEA) is a qualitative test for serum and plasma K2-EDTA, K3–EDTA and Li-Heparin) that combines the results of the Elecsys HE4 assay, Elecsys CA 125 II assay and menopausal status into a numerical score. RCTUEA is intended to aid in assessing whether a premenopausal or postmenopausal woman who presents with an ovarian adnexal mass is at high or low likelihood of finding malignancy on surgery. RCTUEA is indicated for women who meet the following criteria: over age 18; ovarian adnexal mass present for which surgery is planned, and not yet referred to an oncologist. RCTUEA must be interpreted in conjunction with an independent clinical and radiological assessment. The test is not intended as a screening or stand-alone diagnostic assay. The electrochemiluminescence immunoassay “ECLIA” is intended for use on Elecsys and cobas e immunoassay analyzers.
	PRECAUTION: RCTUEA should not be used without an independent clinical/radiological evaluation and is not intended to be a screening test or to determine whether a patient should proceed to surgery. Incorrect use of the RCTUEA calculation for use with the Elecsys HE4 and Elecsys CA 125 II assays carries the risk of unnecessary testing, surgery, and/or delayed diagnosis.
SubstantialEquivalence	The ROMA Calculation Tool Using Elecsys Assays is substantially equivalent to Fujirebio's ROMA (HE4 EIA + ARCHITECT CA 125 IITM) (K103358).
SubstantialEquivalenceComparison	The following table compares the ROMA Calculation Tool Using Elecsys Assays with the predicate device.Continued on next page

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Feature	Fujirebio ROMA	ROMA Calculation Tool UsingElecsys Assays
General Assay Features
Device Type	In vitro diagnostic	In vitro diagnostic
Classification	Class II	Class II
Regulation Number	21 CFR 866.6050 Ovarian adnexalmass assessment score test system	21 CFR 866.6050 Ovarian adnexalmass assessment score test system
Product Usage	Clinical and Hospital laboratories	Clinical and Hospital laboratories
Product Code	ONX	ONX
Panel	Immunology (82)	Immunology (82)
Intended Use/Indications for Use	For In Vitro Diagnostic Use OnlyThe Risk of Ovarian MalignancyAlgorithm (ROMATM) is aqualitative serum test thatcombines the results of HE4 EIA,ARCHITECT CA 125 IITM andmenopausal status into a numericalscore.ROMA is intended to aid inassessing whether apremenopausal or postmenopausalwoman who presents with anovarian adnexal mass is at high orlow likelihood of findingmalignancy on surgery. ROMA isindicated for women who meet thefollowing criteria: over age 18;ovarian adnexal mass present forwhich surgery is planned, and notyet referred to an oncologist.ROMA must be interpreted inconjunction with an independentclinical and radiologicalassessment. The test is notintended as a screening or stand-alone diagnostic assay.	ROMA Calculation Tool UsingElecsys Assays (RCTUEA) is aqualitative test for serum and plasma(K2EDTA, K3EDTA and LiHeparin)that combines the results of theElecsys HE4 assay, Elecsys CA 125 IIassay and menopausal status into anumerical score.RCTUEA is intended to aid inassessing whether a premenopausal orpostmenopausal woman who presentswith an ovarian adnexal mass is athigh or low likelihood of findingmalignancy on surgery. RCTUEA isindicated for women who meet thefollowing criteria: over age 18;ovarian adnexal mass present forwhich surgery is planned, and not yetreferred to an oncologist. RCTUEAmust be interpreted in conjunctionwith an independent clinical andradiological assessment. The test isnot intended as a screening or stand-alone diagnostic assay.The electrochemiluminescenceimmunoassay “ECLIA” is intendedfor use on Elecsys and cobas eimmunoassay analyzers.
Assay Comparison
Feature	Fujirebio ROMA	ROMA Calculation Tool UsingElecsys Assays
General Assay Features
Precautions(ROMA)	Precaution: ROMA (HE4 EIA +ARCHITECT CA 125 II shouldnot be used without anindependent clinical/radiologicalevaluation and is NOT intended tobe a screening test or to determinewhether a patient should proceedto surgery. Incorrect use ofROMA (HE4 EIA + ARCHITECTCA 125 II) carries the risk ofunnecessary testing, surgery,and/or delayed diagnosis.	Precaution: RCTUEA should not beused without an independent clinical/radiological evaluation and is NOTintended to be a screening test or todetermine whether a patient shouldproceed to surgery. Incorrect use ofRCTUEA carries the risk ofunnecessary testing, surgery, and/ordelayed diagnosis.
Assay	Quantitative enzyme linkedimmunosorbent assay	Both Elecsys HE4 and Elecsys CA125 are quantitative sandwichimmunoassays
Analytes	HE4 and CA 125 II	HE4 and CA 125 II
Sampletypes	Serum	Serum and plasma
DetectionProtocol	EIA (HE4) and CMIA (CA 125 II)	ECLIA for CA125 II and HE4
Type of Test	Software algorithm and 2immunoassays	Software algorithm and 2immunoassays

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Continued on next page

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Assessing the likelihood of malignancy assessment in women presenting with an adnexal mass who will undergo surgical intervention

RCTUEA takes into account the results of Elecsys HE4 and Elecsys CA 125 II as well as the menopausal status of woman. The RCTUEA value is used to aid in assessing whether a woman is at high or low likelihood of finding malignancy on surgery.

The effectiveness of RCTUEA was determined in a prospective, multi-center, blinded clinical trial for premenopausal and postmenopausal women presenting with an adnexal mass requiring surgical intervention.

A total of 455 women were evaluable in the study. For each patient, an initial cancer risk assessment (ICRA) was completed by a nurse practitioner, physician assistant or a non-gynecological oncologist who provided the assessment of the patient's mass as benign or malignant based on the information available during their work-up of the patient. The corresponding histopathology reports were collected after surgery. The histopathological classifications of the patients are given in the table below:

	All		Premenopausal		Postmenopausal
Histopathological classification	N	%	N	%	N	%
Benign Pathology	371	81.5	228	91.6	143	69.4
Borderline/ LMP	18	3.9	7	2.8	11	5.3
Epithelial Ovarian Cancer	47	10.3	9	3.6	38	18.4
Non-Epithelial O. C.	2	0.4	0	0	2	1.0
Sex Cord Stroma	2	0.4	0	0	2	1.0
Other Gynecologic Cancer	9	2.0	3	1.2	6	2.9
Endometrial	8	1.802	3	1.2	5	2.5
Leiomyosarcoma	1	1.5	0	0	1	0.4
Other Cancer	7	0.4	1	0.4	6	2.9
Peritoneal Mesothelioma	2	0.2	0	0	2	1.0
Appendix	1	0.2	1	0.4	0	0
Carcinoid Tumor	1	0.2	0	0	1	0.5
Colon	1	0.2	0	0	1	0.5
Malignant Lymphoma	1	0.2	0	0	1	0.5
Pseudomyxoma Peritonel	1	0.2	0	0	1	0.5
Metastatic Cancer	1	0.2	1	0.4	0	0
Pancreatic	1	0.2	1	0.4	0	0
Total	455	100	249	100	206	100

Histopathological classification of the multi-center study patients

Use of RCTUEA for stratification into low and high likelihood groups for finding malignancy on surgery

Using a preoperatively collected serum sample, RCTUEA was determined and the patient was stratified into a low or high likelihood group for finding malignancy on surgery. Samples were tested on the Elecsys e411 analyzer at three US testing sites.

The following cut-off points were used in order to provide a specificity level of 75%: Premenopausal women

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RCTUEA values ≥ 1.14 = High likelihood of finding malignancy RCTUEA values < 1.14 = Low likelihood of finding malignancy Postmenopausal women RCTUEA values ≥ 2.99 = High likelihood of finding malignancy RCTUEA values < 2.99 = Low likelihood of finding malignancy

The reported results include the likelihood and associated RCTUEA score on a scale of 0-10 for premenopausal and postmenopausal women.

The stratification of patients presenting with an adnexal mass into high likelihood of malignant disease (epithelial ovarian cancer), borderline or low malignant potential (LMP) tumors and other gynecological and non-gynecological cancers, using RCTUEA results above the cut-points of ≥ 1.14 for premenopausal and ≥ 2.99 for postmenopausal women by histopathology is shown in the table below:

	Premenopausaln=249	Postmenopausaln=206	Alln=455
All EOC	9/91 (100%)	34/381 (89.5%)	43/47 (91.5%)
EOC Stage I+II	3/3 (100%)	5/9 (55.6%)	8/12 (66.7%)
EOC Stage III+IV	5/5 (100%)	28/28 (100%)	33/33 (100%)
LMP Tumors	4/7 (57.1%)	9/11 (81.8%)	13/18 (72.2%)
Other Cancers2	2/5 (40%)	9/14 (64.2%)	11/19 (57.9%)
All cancers&LMP Tumors	15/21 (71.4%)	52/63 (82.5%)	67/84 (79.8%)

1 One EOC patient was unstaged 2 non-epithelial cancer, other gynecologic and non-gynecologic cancers

The performance of RCTUEA for stratification into low likelihood and high likelihood groups for premenopausal and postmenopausal women with epithelial ovarian cancer (EOC) only is shown in the table below:

	Premenopausal (N=237)		Postmenopausal (N=181)
	Estimate	95% CI	Estimate	95% CI
Sensitivity	100% (9/9)	66.4% 100%	89.5% (34/38)	75.2% 97.1%
Specificity	77.6% (177/228)	71.7% 82.9%	82.5% (118/143)	75.3% 88.4%
TP-FP1	77.6%	72.1% 83.2%	72.0%	60.2% 83.8%
PPV2	15.0% (9/60)	7.1% 26.6%	57.6% (34/59)	44.1% 70.4%
NPV3	100.0% (177/177)	97.9% 100%	96.7% (118/122)	91.8% 99.1%
Prevalence	3.8% (9/237)		21.0% (38/181)

1TP-FP = True Positive rate-False Positive rate, 2PV= Positive Value, 3NPV = Negative Predictive Value

Adjunctive use of RCTUEA with Initial Cancer Risk Assessment (ICRA) for stratification into high likelihood and low likelihood for malignancy

The performance for the adjunctive use of RCTUEA with ICRA (ICRA and/or RCTUEA being positive for high likelihood of finding malignancy on surgery) for

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diagnosis of EOC including LMP, sensitivity for malignancy increased from 76.9% to 90.8%. Specificity for malignancy decreased from 84.4% to 70.4%. PPV for adjunctive use of ICRA and RCTUEA decreased from 46.3% to 34.9% due to the increase in the number of false positive tests. However, NPV of the adjunctive use of ICRA and RCTUEA increased from 95.4% to 97.8%. This observed increase in NPV was statistically significant, (P=0.0000) supporting the adjunctive use of RCTUEA with ICRA effective in ruling out cancer.

Performance of RCTUEA versus ICRA for Malignant and Non-Malignant cohorts as determined by Pathology

Malignancy by Pathology				No Malignancy by Pathology
		ICRA			ICRA
		Pos	Neg	Total		Pos	Neg	Total
RCTUEA	Pos	47	9	56		Pos	24	52	76
	Neg	3	6	9		Neg	34	261	295
	Total	50	15	65		Total	58	313	371

All malignancies found including EOC, non-epithelial ovarian cancer, other gynecologic and nongynecologic cancers

Performance of RCTUEA for Diagnosis of EOC including LMP

	ICRA			RCTUEA		Adjunctive
	Estimate	95% CI	Estimate	95% CI	Estimate	95% CI
Sensitivity	76.9%50/65	64.8% 86.5%	86.2%56/65	75.3% 93.5%	90.8%59/65	81.0% 96.5%
Specificity	84.4%313/371	80.3% 87.9%	79.5%295/371	75.0% 83.5%	70.4%261/371	65.4% 75.0%
PPV	46.3%50/108	36.7% 56.2%	42.4%56/132	33.9% 51.3%	34.9%59/169	27.8% 42.6%
NPV	95.4%313/328	92.6% 97.4%	97.0%295/304	94.5% 98.6%	97.8%261/267	95.2% 99.2%
TP-FPa	61.3%	50.2% 72.4%	65.7%	56.1% 75.2%	61.1%	52.5% 69.7%
PLRb	4.92	3.75 6.45	4.21	3.37 5.26	3.06	2.57 3.65
NLRc	0.27	0.18 0.43	0.17	0.09 0.32	0.13	0.06 0.28
Prevalence	14.9% (65/436)

ª TP-True Positive; FP-False Positive Likelihood Ratio° NLR-Negative Likelihood Ratio

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Standard/	In addition to FDA guidance regarding 510(k) submissions, the
Guidance	following standards were used for the performance studies.
Document
Reference	Evaluation of Precision Performance of QuantitativeMeasurement Methods; CLSI document EP5-A2, August2004.
	Method Comparison and Bias Estimation Using Patient

Method Comparison and Bias Estimation Using Patient
Samples, CLSI document EP9-A2-IR, July 2010. .

Regulation Number and Section

§ 866.6050 Ovarian adnexal mass assessment score test system.

(a)
Identification. An ovarian/adnexal mass assessment test system is a device that measures one or more proteins in serum or plasma. It yields a single result for the likelihood that an adnexal pelvic mass in a woman, for whom surgery is planned, is malignant. The test is for adjunctive use, in the context of a negative primary clinical and radiological evaluation, to augment the identification of patients whose gynecologic surgery requires oncology expertise and resources.(b)
Classification. Class II (special controls). The special control for this device is FDA's guidance document entitled “Class II Special Controls Guidance Document: Ovarian Adnexal Mass Assessment Score Test System.” For the availability of this guidance document,see § 866.1(e).(c)
Black box warning. Under section 520(e) of the Federal Food, Drug, and Cosmetic Act these devices are subject to the following restriction: A warning statement must be placed in a black box and must appear in all advertising, labeling, and promotional material for these devices. That warning statement must read: