(142 days)
For the qualitative determination of IgM antibodies in human serum to Epstein Barr (recombinant) early antigen diffuse (EA-D) antigen. The & EA-D IgM assay should be used in conjunction with other Epstein-Barr serologies (VCA IgM, VCA IgG, EBNA-1 IgG, EBNA-1 IgM, EA-D IgG and heterophile) as an aid in the diagnosis of infectious mononucleosis. The test can be performed either manually or in conjunction with the MAGO PLUS The Automated EIA Processor.
The & EA-D IgM ELISA Kit is an enzyme-linked immunosorbent assay (ELISA) for the detection of IgM antibodies to Epstein-Barr Early antigen diffuse in human serum.
Here's an analysis of the provided text regarding the acceptance criteria and study for the EA-D IgM ELISA Kit:
The document does not explicitly state pre-defined acceptance criteria for the device's performance. Instead, it presents the results of its performance characteristics study. The acceptance for market clearance seems to be based on "substantial equivalence" to legally marketed predicate devices, implying that the observed performance falls within an acceptable range compared to those predicates, even if specific numerical targets aren't listed here.
However, we can infer the "reported device performance" from the study results.
1. A table of acceptance criteria and the reported device performance
As stated, explicit acceptance criteria are not presented in the document. The table below outlines the reported performance from the study, which would have been evaluated against a benchmark for substantial equivalence.
| Performance Metric | Reported Device Performance | Comments |
|---|---|---|
| Clinical Performance (vs. Serological Status) | ||
| Relative Specificity (Convalescent) | 94.9% (95% CI: 88.5-98.3%) | Based on 93/98 sera |
| Relative Sensitivity (Current Infection) | 45.9% (95% CI: 29.5-63.1%) | Based on 17/37 sera |
| Relative Specificity (Seronegative) | 96.7% (95% CI: 82.8-99.9%) | Based on 29/30 sera |
| Overall Agreement | 84.2% (95% CI: 78.7-89.8%) | Based on 139/165 sera (equivocal excluded) |
| Precision (Internal Site #1) | Coefficient of Variation (CV%) | |
| Intra-Assay CV% (Positive samples) | 4.53% - 12.81% | Range across 4 positive sera and 3 runs |
| Intra-Assay CV% (Negative samples) | 35.23% - 46.08% | Range across 2 negative sera and 3 runs |
| Inter-Assay CV% (Positive samples) | 5.35% - 11.20% | Range across 4 positive sera |
| Inter-Assay CV% (Negative samples) | 34.16% - 42.74% | Range across 2 negative sera |
| Inter-Site Precision | Coefficient of Variation (CV%) | |
| Inter-Site CV% (Positive samples) | 9.10% - 17.32% | Range across 4 positive sera (n=90) |
| Inter-Site CV% (Negative samples) | 30.28% - 31.41% | Range across 2 negative sera (n=90) |
| Correlation (Manual vs. MAGO Plus) | ||
| Pearson's Correlation Coefficient | 0.975 | Between manual and MAGO Plus results (128 samples) |
| Specificity (Cross-Reactivity) | Some expected | Non-reactive for anti-EA-D IgM in VZV, CMV, HSV positive sera; suggests some cross-reactivity may occur with these analytes. |
| MAGO Plus Precision (Site #2) | Coefficient of Variation (CV%) | |
| Intra-Assay CV% (Positive samples) | 3.76% - 16.10% | Range across 4 positive sera and 3 runs |
| Intra-Assay CV% (Negative samples) | 0.00% - 37.16% | Range across 2 negative sera and 3 runs |
| Inter-Assay CV% (Positive samples) | 4.35% - 11.76% | Range across 4 positive sera |
| Inter-Assay CV% (Negative samples) | 20.86% - 30.51% | Range across 2 negative sera |
2. Sample sized used for the test set and the data provenance
- Test Set Sample Size: 176 patient sera were used for the clinical performance study.
- Data Provenance: The data used was from retrospective sera from patients. The country of origin is not explicitly stated, but given the applicant and reporting of a 510(k) to the FDA, it is highly likely to be from the USA.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts
The ground truth for the test set was established by characterizing the 176 frozen retrospective sera using "commercially available kits for VCA IgM, VCA IgG, EBNA IgG and heterophile antibodies."
- Number of Experts: Not applicable, as the "ground truth" (or reference standard) was established using other commercial serological assays, not by expert interpretation.
- Qualifications of Experts: Not applicable.
4. Adjudication method for the test set
The concept of an "adjudication method" as typically applied in scenarios involving multiple human readers (e.g., 2+1, 3+1 for discrepancies) is not relevant here. The ground truth for the test set was determined by the results of other commercial serological assays, which are considered objective measurements, not subjective interpretations requiring adjudication.
5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance
- MRMC Study Done: No, an MRMC comparative effectiveness study was not done.
- Effect Size of Human Readers Improvement with/without AI: Not applicable, as this is an in vitro diagnostic device for antibody detection, not an imaging analysis or interpretive AI system that assists human readers.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done
Yes, the primary clinical performance study (Section A) evaluates the device in standalone mode. The results of the Is-EBV-EA-D IgM Test Kit were directly compared to the classification of patient sera based on other commercial EBV serologies. While a technician performs the test, the result (positive, negative, equivocal) is generated by the kit itself, making it a standalone assessment of the device's diagnostic capability. The section on manual vs. MAGO Plus correlation also demonstrates standalone performance for both methods.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)
The ground truth for the clinical performance study was established using a combination of commercially available serological assays for Epstein-Barr Virus (EBV) antibodies. This allowed for the classification of sera into "convalescent," "current infection," and "seronegative" categories based on established serological patterns for EBV infection. It's a form of clinical reference standard based on established serology.
- Specifically:
- Convalescent (past infection): Positive for VCA IgG and/or EBNA IgG antibodies; negative for VCA IgM and heterophile antibody.
- Seronegative: Negative for VCA IgG, VCA IgM, EBNA IgG, and heterophile antibody.
- Current (recent) infection: Positive for VCA IgM and/or heterophile antibody; negative for EBNA IgG.
8. The sample size for the training set
The document does not explicitly describe a separate "training set" for the development of the EA-D IgM ELISA Kit. The provided studies focus on the performance evaluation of the developed device. For in vitro diagnostic kits, the "training" (development and optimization) phase is usually internal and not detailed in 510(k) summaries in the same way as machine learning models. Therefore, the sample size for a training set (in the ML sense) is not reported.
9. How the ground truth for the training set was established
As there is no distinct "training set" described in the context of machine learning model development, the method for establishing its ground truth is not applicable/not reported in this 510(k) summary. The development of an ELISA kit involves biochemical optimization and formulation, rather than algorithmic training on labeled data in the way an AI/ML model would.
{0}------------------------------------------------
NOV 2 5 1998
510k Summary of Safety and Effectiveness
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.
The assigned 510(k) number is:
Applicant Information:
| Date Prepared: | March 23, 1998 |
|---|---|
| Name: | Columbia Bioscience, Inc. |
| Address: | 8775 M Centre Park Drive, #559Columbia, MD 21045 |
| Contact Person: | Norman Jenkins |
|---|---|
| PhoneNumber. | 410-995-0450 |
| Fax Number. | 410-995-0448 |
Device Information:
| Trade Name: | EA-D IgM ELISA Kit |
|---|---|
| Common Name. | EA-D IgM EIA Test |
| Classification Name; | Epstein-Barr Virus |
Equivalent Device: EBV Serology
Device Description: The & EA-D IgM ELISA Kit is an enzyme-linked immunosorbent assay (ELISA) for the detection of IgM antibodies to Epstein-Barr Early antigen diffuse in human serum.
Intended Use: For the qualitative determination of IgM antibodies in human serum to Epsien Barr Virus (recombinant) Early antigen (EA-D) antigen. The & EA-D IgG assay should be used in conjunction with other Epstein-Barr serologies (VCA IgM. VCA IgG. EBNA-1 IgM and heterophile) as an aid in the diagnosis of infectious mononucleosis. The test can be performed either manually or in conjunction with the MAGO PLUS TM Automated EIA Processor.
Principle of Procedure:
The & EA-D IgG ELISA Kit is an enzyme-linked immunosorbent assay to detect IgG to EA-D in human serum. Recombinant EA-D antigen is attached to a solid phase (microtiter well). Diluted test sera are added to each well. If antibodies which recognize the. EA-D antigen are present in the patient sample they will bind to the antigen in the well. After incubation, the wells are washed to remove unbound antibody. An enzyme labeled anti-human immunoglobulin (conjugate) is added to each test well. If antibody is present the enzyme-linked antibody will bind to it. After incubation, the wells are washed to remove unbound conjugate. A substrate solution is then added to each well. If enzyme is present from prior step, the reaction is stopped and the, color intensity is measured photometrically producing an indirect detection of the specific antibody present in the patient sample.
{1}------------------------------------------------
Performance Characteristics
A. Clinical Sensitivity and Specificity Using Characterized Sera
Frozen retrospective sera from one hundred and seventy-six patients were characterized using commercially available kits for VCA IgM, VCA IgG, EBNA IgG and heterophile antibodies. Based on the results of this testing, the patient sera were characterized as follows:
-
102 sera were characterized as convalescent (past infection). These were positive for VCA IgG and/or EBNA IgG antibodies and negative for VCA IgM and heterophile antibody.
-
32 sera were characterized as scronegative. These were negative for VCA IgG, VCA IgM, EBNA IgG and heterophile antibody.
-
42 sera were characterized as having a current (recent) infection. These were positive for VCA IgM and/or heterophile antibody and were negative for EBNA IgG.
All 176 sera were then tested by an independent clinical commercial laboratory using the Is-EBV-EA-D IgM Test Kit. The results obtained are shown in Table 2:
| TABLE 2 | EBV Serological Status | |||
|---|---|---|---|---|
| Convalescent | Current Infection | Seronegative | ||
| POSITIVE | 5 | 17 | . 1 | |
| Is-EBV-EA-D-IgM | NEGATIVE | 93 | 20 | 29 |
| *EQUIVOCAL | 4 | 5 | 2 |
| 95% CI | |||
|---|---|---|---|
| Relative Specificity (Convalescent) | 93/98 | = 94.9% | 88.5-98.3% |
| Relative Sensitivity (Current Infection) | 17/37 | = 45.9% | 29.5-63.1% |
| Relative Specificity (Seronegative) | 29/30 | = 96.7% | 82.8-99.9% |
| Overall Agreement | 139/165 | = 84.2% | 78.7-89.8% |
ERV Serological Status
- Equivocal results were excluded from calculations
NOTE : Please be advised that 'relative' refers to the comparison of the assay's results to that of a similar assay. There was not an attempt to correlate the assay's results with disease presence or absence. No judgment can be made on the comparison's accuracy to predict disease. Since the above studies were performed on a pre-selected, retrospective population, no calculations for the assay's positive predictive value may be done or inferred.
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B.Precision
Todclerminethe precisionofthels-EBV-EA-DIgMTestKit, fourpositive and wonegativesera were assayed ten timescachinthreedifferentrunsatthreedifferentsites. The3sitesinclude: themanufacturer, arescarchanddevelopmentlaboratory,andaclinicalcommerciallaboratory. Theintra-andinterassayprecisionobtainedateachsiteis showninTables3,4and5.TheInter-SiteprecisionisshowninTable6.
| SERUM | INTRA-ASSAY RUN 1 | INTRA-ASSAY RUN 2 | INTRA-ASSAY RUN 3 | INTERASSAY | |||||
|---|---|---|---|---|---|---|---|---|---|
| MEAN INDEX | CV% | MEAN INDEX | CV% | MEAN INDEX | CV% | MEAN INDEX | CV% | ||
| A (POS) | 6.59 | 5.42 | 6.37 | 4.53 | 6.25 | 5.17 | 6.40 | 5.35 | |
| B (POS) | 1.86 | 12.60 | 1.79 | 10.84 | 1.95 | 6.18 | 1.87 | 10.46 | |
| C (POS) | 2.90 | 10.05 | 2.67 | 7.31 | 2.61 | 9.00 | 2.73 | 9.77 | |
| D (POS) | 1.37 | 8.92 | 1.38 | 12.45 | 1.41 | 12.81 | 1.39 | 11.20 | |
| E (NEG) | 0.14 | 44.84 | 0.15 | 39.58 | 0.16 | 46.08 | 0.15 | 42.74 | |
| F (NEG) | 0.44 | 15.23 | 0.45 | 39.42 | 0.32 | 35.23 | 0.40 | 34.16 | |
| CAL | 0.97 | 10.49 | n = 9 | ||||||
| PC | 1.65 | 12.75 | n = 3 | ||||||
| NC | 0.29 | 38.40 | n = 3 |
TABLE 4 : Site #2- Intra-Assay and Interassay Precision
| SERUM | INTRA-ASSAY RUN 1 | INTRA-ASSAY RUN 2 | INTRA-ASSAY RUN 3 | INTERASSAY | |||||
|---|---|---|---|---|---|---|---|---|---|
| MEANINDEX | MEANINDEX | CV% | MEANINDEX | CV% | MEANINDEX | CV% | MEANINDEX | CV% | |
| A (POS) | 6.328 | 6.78 | 5.514 | 4.34 | 6.055 | 3.85 | 5.966 | 7.68 | |
| B (POS) | 1.813 | 9.32 | 1.580 | 10.07 | 1.722 | 6.65 | 1.705 | 10.21 | |
| C (POS) | 2.465 | 5.70 | 2.376 | 17.21 | 2.521 | 6.15 | 2.454 | 10.72 | |
| D (POS) | 1.261 | 4.89 | 1.118 | 6.07 | 1.219 | 3.78 | 1.199 | 6.97 | |
| E (NEG) | 0.144 | 28.01 | 0.155 | 16.49 | 0.150 | 14.21 | 0.149 | 19.71 | |
| F (NEG) | 0.289 | 15.47 | 0.341 | 8.87 | 0.308 | 10.00 | 0.313 | 13.11 | |
| CAL | 1.001 | 4.69 | n = 18 | ||||||
| PC | 1.564 | 12.03 | n = 12 | ||||||
| NC | 0.303 | 4.72 | n = 12 |
| TABLE 5 : Site #3 - Intra-assay and Interassay Precision | ||||
|---|---|---|---|---|
| -- | -- | -- | ---------------------------------------------------------- | -- |
| SERUM | INTRA-ASSAY RUN 1 | INTRA-ASSAY RUN 2 | INTRA-ASSAY RUN 3 | INTERASSAY | ||||
|---|---|---|---|---|---|---|---|---|
| MEANINDEX | CV% | MEANINDEX | CV% | MEANINDEX | CV% | MEANINDEX | CV% | |
| A (POS) | 6.35 | 11.01 | 6.53 | 12.63 | 6.05 | 11.29 | 6.31 | 11.74 |
| B (POS) | 1.98 | 9.08 | 1.90 | 10.74 | 1.91 | 11.87 | 1.93 | 10.36 |
| C (POS) | 2.63 | 16.02 | 2.59 | 15.59 | 2.52 | 17.40 | 2.58 | 15.86 |
| D (POS) | 1.55 | 20.22 | 1.49 | 26.10 | 1.42 | 14.80 | 1.49 | 20.67 |
| E (NEG) | 0.13 | 15.27 | 0.12 | 19.99 | 0.13 | 23.17 | 0.13 | 19.85 |
| F (NEG) | 0.29 | 15.16 | 0.24 | 15.18 | 0.36 | 10.88 | 0.29 | 21.96 |
| CAL | 1.00 | 11.59 | ||||||
| PC | 1.42 | 6.45 | ||||||
| NC | 0.30 | 5.77 |
Table 6 : Inter-Site Precision
| SERUM(n=90) | INTER-SITE | |
|---|---|---|
| MEANINDEX | CV% | |
| A (POS) | 6.23 | 9.10 |
| B (POS) | 1.83 | 11.51 |
| C (POS) | 2.58 | 12.97 |
| D (POS) | 1.36 | 17.32 |
| E (NEG) | 0.14 | 31.41 |
| F (NEG) | 0.34 | 30.28 |
| CAL (n=36) | 0.99 | 8.21 |
| LPC (n=18) | 1.55 | 11.87 |
| NC (n=18) | 0.30 | 13.42 |
{3}------------------------------------------------
C. Specificity with Potentially Cross-Reactive Sera
Thirteen sera, non-reactive (negative) for IgM antibodies to EA-D in the Is-EBV-EA-D IgM Test Kit, were tested by EIA for IgM antibody to varicclla zoster, cytomegalovirus and herpes simplex virus. 4/4 anti-VZV IgM positive scra were non-reactive for anti-EA-D IgM; 3/5 anti-CMV IgG positive sera were non-reactive for anti-EA-D IgM and 4/4 anti-HSV positive scra were non-reactive for anti-EA-G IgM. This suggests that some cross-reactivity should be expected with the Is-FA-D IgM Test Kit from these analytes.
D. Correlation of Manual and MAGO Plus Results
The Is-I'D V-EA-D IgM Test Kit has been developed for automated as well as manual use. To demonstrate the equivalence of the manual and MAGO Plus procedures, the results of 128 serum samples tested by both methods were plotted. A scattergram and regression line of the results obtained with 95% confidence intervals is shown in Figure 3. The data indicate good correlation with a Pearson Correlation Coefficient of 0.975.
Image /page/3/Figure/4 description: This image is a scatter plot comparing "MAGO PLUS INDEX VALUES" on the y-axis and "MANUAL INDEX VALUES" on the x-axis. The data points are clustered around a regression line, indicating a positive correlation between the two variables. The equation of the regression line is given as Y = 0.0657 + 0.9423 X, and the correlation coefficient (r) is 0.975, suggesting a strong linear relationship.
FIGURE 3 : Manual and MAGO Plus Result Correlation
E. MAGO Plus Precision
The precision of the assay when performed on the MAGO Plus Automated EIA Processor was determined by assaying six sera ten times each in three different runs. Table 7 shows the intra-and interassay precision obtained using the MAGO Plus.
TABLE 7 : Site #2- Intra-Assay and Interassay Precision - MAGO Plus
| SERUM | INTRA-ASSAY RUN 1MEANINDEX | INTRA-ASSAY RUN 1CV% | INTRA-ASSAY RUN 2MEANINDEX | INTRA-ASSAY RUN 2CV% | INTRA-ASSAY RUN 3MEANINDEX | INTRA-ASSAY RUN 3CV% | INTERASSAYMEANINDEX | INTERASSAYCV% |
|---|---|---|---|---|---|---|---|---|
| A (POS) | 6.1 | 3.76 | 5.8 | 4.29 | 5.8 | 3.98 | 5.9 | 4.35 |
| B (POS) | 1.8 | 6.38 | 1.7 | 7.27 | 1.8 | 8.12 | 1.8 | 7.44 |
| C (POS) | 2.7 | 5.51 | 2.5 | 7.23 | 2.6 | 7.49 | 2.6 | 6.97 |
| D (POS) | 1.4 | 16.10 | 1.3 | 7.77 | 1.3 | 8.34 | 1.3 | 11.76 |
| E (NEG) | 0.1 | 37.16 | 0.1 | 28.75 | 0.1 | 0.00 | 0.1 | 30.51 |
| F (NEG) | 0.3 | 23.80 | 0.3 | 20.45 | 0.3 | 15.06 | 0.3 | 20.86 |
| CAL | 1.0 | 2.80 | ||||||
| PC | 1.7 | 3.50 | ||||||
| NC | 0.4 | 0.00 |
{4}------------------------------------------------
Image /page/4/Picture/1 description: The image shows the seal of the Department of Health & Human Services (HHS) of the United States of America. The seal features the department's name encircling a symbol. The symbol consists of a stylized caduceus, which is a traditional symbol of medicine, with three figures representing health and human services. The text is arranged in a circular pattern around the symbol.
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
NOV 25 1998
Norman Jenkins President Columbia Bioscience, Inc. 8775 M Centre Park Drive, #559 Columbia, Maryland 21045
Re: K982350 Device: EA-D IgM ELISA Test System Dated: September 22, 1998 Received: September 28, 1998
Dear Mr. Jenkins:
We have reviewed your Section 510(k) notification of intent to market the device referenced above and we 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). 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.
If your device is classified (see above) into either class II (Special Controls) or class III (Premarket Approval), it may be subject to such additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 895. A substantially equivalent determination assumes compliance with the Current Good Manufacturing Practice requirements, as set forth in the Quality System Regulation (QS) for Medical Devices: General regulation (21 CFR Part 820) and that, through periodic OS inspections, the Food and Drug Administration (FDA) will verify such assumptions. Failure to comply with the GMP regulation may result in regulatory action. In addition. FDA may publish further announcements concerning your device in the Federal Register. Please note: this response to your premarket notification submission does not affect any obligation you might have under sections 531 through 542 of the Act for devices under the Electronic Product Radiation Control provisions, or other Federal laws or regulations.
{5}------------------------------------------------
Page 2
Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88), this device may require a CLIA complexity categorization. To determine if it does, you should contact the Centers for Disease Control and Prevention (CDC) at (770)488-7655.
This letter will allow you to begin marketing your device as described in your 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.
If you desire specific advice for your device on our labeling regulation (21 CFR Part 801 and additionally 809.10 for in vitro diagnostic devices), please contact the Office of Compliance at (301) 594-4588. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at (301) 594-4639. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers Assistance at its toll free number (800) 638-2041 or at (301) 443-6597 or at its internet address "http://www.fda.gov/cdrh/dsmamain.html"
Sincerely yours,
Steven Butman
Steven I. Gutman, M.D., M.B.A. Director Division of Clinical Laboratory Devices Office of Device Evaluation Center for Devices and Radiological Health
Enclosure
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Page 1 of 1
510(k) Number: Not Known
Device Name: & EA-D IgM ELISA
Indications For Use: For the qualitative determination of IgM antibodies in human serum to Epstein Barr (recombinant) early antigen diffuse (EA-D) antigen. The & EA-D IgM assay should be used in conjunction with other Epstein-Barr serologies (VCA IgM, VCA IgG, EBNA-1 IgG, EBNA-1 IgM, EA-D IgG and heterophile) as an aid in the diagnosis of infectious mononucleosis. The test can be performed either manually or in conjunction with the MAGO PLUS The Automated EIA Processor.
PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED) ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Concurrence of CDRH, Office of Device Evaluation (ODE)
Prescription Use (Per 21 CFR 801.109)
OR
Over-The Counter Use (Optional Format 1-2-96)
Woody Dubois
inical I aboratory Devices 510(k) Number
§ 866.3235 Epstein-Barr virus serological reagents.
(a)
Identification. Epstein-Barr virus serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to Epstein-Barr virus in serum. The identification aids in the diagnosis of Epstein-Barr virus infections and provides epidemiological information on diseases caused by these viruses. Epstein-Barr viruses are thought to cause infectious mononucleosis and have been associated with Burkitt's lymphoma (a tumor of the jaw in African children and young adults) and postnasal carcinoma (cancer).(b)
Classification. Class I (general controls).