lndications for Use :The Diamedix Is-dsDNA an Enzyme Immunoassay (ElA) for the detection and quantitative determination of IgG antibodies in human serum to DNA antigen as an aid in the diagnosis of systemic lupus erythematosus in patients with clinical signs of the disease. These reagents can be used either manually or in conjunction with the MAGO® Automated EIA Processor.

Device Description

The Is-dsDNA Test Kit System is an enzyme-linked immunosorbent assay (ELISA) for the detection and quantitation of IgG to DNA in human serum

AI/ML Overview

Here's an analysis of the provided text regarding the acceptance criteria and study for the Diamedix Is-dsDNA Test System:

Acceptance Criteria and Device Performance

The document does not explicitly state pre-defined quantitative "acceptance criteria" for the study beyond implicitly demonstrating performance relative to a comparative method and typical characteristics for diagnostic assays (linearity, precision, cross-reactivity). The summary focuses on presenting the observed performance rather than comparing it against specific pre-set numerical targets for approval.

However, based on the provided performance characteristics, we can infer some desired outcomes that would constitute "meeting acceptance criteria" in a general sense for a diagnostic device: good sensitivity and specificity, linearity, precision, and lack of significant cross-reactivity.

Here's a table summarizing the reported device performance:

Performance Metric	Acceptance Criteria (Inferred from industry norms for diagnostic kits)	Diamedix Is-dsDNA Test System Performance (Manual)	Diamedix Is-dsDNA Test System Performance (MAGO)
Relative Sensitivity (vs. comparative method)	Typically high (e.g., >80-90%)	94.9% (37/39) [95% CI: 82.7-99.4]	90.6% (29/32) [95% CI: 75.0-98.0]
Relative Specificity (vs. comparative method)	Typically high (e.g., >95%)	100.0% (199/199) [95% CI: 98.2-100]	100.0% (201/201) [95% CI: 98.2-100.0]
Overall Agreement	Typically high (e.g., >90%)	99.2% (236/238) [95% CI: 97.0-99.9]	98.7% (230/233) [95% CI: 96.3-99.7]
Linearity (R-squared)	High (e.g., >0.95)	0.9821 (Manual)	0.9961 (MAGO)
Intra-assay Precision (%CV)	Low (e.g., <15-20% for positive samples)	3.6% - 12.9% (Positive Sera, Manual)	10.4% - 14.9% (Positive Sera, MAGO)
Inter-assay Precision (%CV)	Low (e.g., <15-20% for positive samples)	6.9% - 13.0% (Positive Sera, Manual)	6.1% - 14.8% (Positive Sera, MAGO)
Cross-reactivity	Minimal/None with other autoantibodies	No cross-reactivity observed with tested autoantibodies (SSA, SSB, Sm/RNP, Jo-1, Scl-70). Some samples positive for ssDNA also tested positive for dsDNA, but these were also confirmed by other dsDNA tests.

Study Details

Sample sizes used for the test set and the data provenance:
- Comparison Testing:
  - Normal Blood Donors: 200 sera
  - SLE Patients: 50 sera
  - Provenance: "Normal donor sera collected in South Florida." The provenance of the SLE patient sera is not explicitly stated, but it's likely from the same geographical region or collected similarly. The study is retrospective as it uses collected sera.
- Precision Testing: Six different sera (positive and negative) and kit calibrator/controls.
- Cross-reactivity Testing:
  - 11 samples containing other autoantibodies (SSA, SSB, Sm/RNP, Jo-1, Scl-70) with no dsDNA antibodies.
  - 49 samples containing varying levels of single-stranded DNA (ssDNA).
Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
The document does not specify the number or qualifications of experts used to establish the ground truth for the test set. For the comparison study, the "ground truth" for Systemic Lupus Erythematosus (SLE) status was based on clinical diagnosis (patients identified as "SLE patients") and confirmed by a "comparative method" (another commercially available anti-dsDNA test kit). For cases where the Diamedix Is-dsDNA and the comparative method disagreed, a "referee method" was used, but details of this method or the experts involved are not provided.
Adjudication method for the test set:
For the comparison testing, if the Is-dsDNA test and the comparative method disagreed, a "referee method" was used. The specific details of this referee method or how disagreements were resolved if the referee method itself was equivocal are not provided. The phrase "two were positive and one was negative" (for manual testing disagreements) and "one was negative and one was positive" (for MAGO testing disagreements) implies a form of adjudication, but not a specific 2+1 or 3+1 structure. Equivocal/borderline results from the initial testing were excluded from the sensitivity, specificity, and agreement calculations: 12 for manual and 16 for MAGO.
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:
No, a multi-reader multi-case (MRMC) comparative effectiveness study was not conducted. This device is an in-vitro diagnostic (IVD) test kit (ELISA), not an AI-powered image analysis or interpretation tool that would involve human "readers" in the context of MRMC studies. The "MAGO Automated Processor" mentioned is an automation platform for running the ELISA, not an AI for interpretation.
If a standalone (i.e., algorithm only without human-in-the-loop performance) was done:
Yes, in essence. The performance metrics (sensitivity, specificity, linearity, precision, cross-reactivity) are reported for the device itself, both when operated manually and when operated using the "MAGO Automated Processor." These reflect the standalone performance of the test kit in detecting dsDNA antibodies in serum samples. There isn't an "algorithm" in the typical AI sense, but rather the performance of the chemical assay.
The type of ground truth used:
- Clinical Diagnosis: For the main comparison study, patients were categorized as "normal blood donors" or "SLE patients," implying clinical diagnosis was the primary ground truth for disease status.
- Comparative Method/Referee Method: The actual "truth" of dsDNA antibody presence was established by comparison to another commercially available anti-dsDNA test kit (the "comparative method") and, in cases of disagreement, a "referee method." The specific nature of this referee method is not detailed, but it would presumably be a highly reliable, perhaps more invasive or gold-standard, diagnostic approach for dsDNA antibodies.
- Known Autoantibody Status: For cross-reactivity, samples with known presence (or absence) of other autoantibodies (e.g., SSA, SSB) and ssDNA were used, indicating that this aspect of ground truth was derived from other established diagnostic tests.
The sample size for the training set:
The document does not provide information about a specific "training set" for the device in the context of machine learning or AI. This is an ELISA test kit, and its development would typically involve optimization and validation iterations rather than distinct training and test sets as understood in AI/ML. The "inhouse reference standard" mentioned in linearity testing suggests internal calibration development, but no specific training set size is given.
How the ground truth for the training set was established:
As there's no explicitly defined "training set" in the AI/ML sense, this question is not fully applicable. The development of an ELISA kit like this typically involves establishing reference standards (like the "Wo/80 WHO Standard" mentioned) and optimizing the assay components and parameters. The ground truth for such development would be based on these established international standards and internal characterization using known positive and negative samples, but the details of how those internal standards were established are not provided.

Summary

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K974694

MAR - 3 1998

Appendix E. 510(k) Summary of Safety and Effectiveness

The following section is included as required by the Safe Medical Device Act (SMDA) of 1990.

Name: Address:

ﺔ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤ

Diamedix Corporation 2140 N. Miami Avenue Miami, FL 33127

ﻣﻌﻤﻮﺩ

Contact Person: Phone Number: Fax Number:

Dr. Lynne Stirling 305-324-2354 305-324-2585

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510(k) 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: _ K974694

Applicant Information:

Date Prepared:	December 15, 1997
Name:	Diamedix Corporation
Address:	2140 N. Miami AvenueMiami, FL 33127

Contact Person:	Dr. Lynne Stirling
Phone Number:	305-324-2354
Fax Number:	305-324-2585

Device Information:

Trade Name:	Is-dsDNA Test System
Common Name:	Anti-DNA EIA Test
Classification Name:	Anti-DNA Antibody

い

Equivalent Device:

varelisa dsDNA Antibodies

Device Description: The Is-dsDNA Test Kit System is an enzyme-linked immunosorbent assay (ELISA) for the detection and quantitation of IgG to DNA in human serum

Intended Use: The assay is intended for use in detecting IgG antibodies to dsDNA in a single human serum sample. The results of the assay are to be used as an aid in the diagnosis of SLE.

Principle of the Procedure:

The Is-dsDNA Test System is an enzyme-linked immunosorbent assay to detect IgG toDNA in human serum. Purified DNA is attached to a solid phase microtiter well. Diluted test sera are added to each well. If antibodies which recognize the DNA 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 measure of the specific antibody present in the patient sample.

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SUMMARY OF SAFETY AND EFFECTIVENESS

Performance Charactistics

A. Comparison Testing

The Diamedix Is-dsDNA Test Kit was evaluated relative to another commercially available anti-dsDNA test kit that is also standardized against the Wo/80 WHO Standard. Two hundred sera from normal blood donors and 50 sera from SLE patients were tested by the Is-dsDNA test kit and the comparative method. Testing was performed both manually and using the MAGO Automated Processor. Results are shown in Table 1.

TABLE 1		Manual		MAGO
	# of Sera	%	95% CI	# of Sera	%	95% CI
Relative Sensitivity	37/39	94.9	82.7-99.4	29/32	90.6	75.0-98.0
Relative Specificiity	199/199	100.0	98.2-100	201/201	100.0	98.2-100.0
Overall Agreement	236/238*	99.2	97.0-99.9	230/233**	98.7	96.3-99.7

12 equivocal/borderline results excluded from calculations

ﺎﺕ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟ

** 16 equivocal/borderline results excluded from calculations; I sample QNS

For manual testing there were three samples negative by the Is-dsDNA and positive by the comparative method. When these samples were tested by a referee method two were positive and one was negative. For MAGO testing there were two samples that were negative in the Is-dsDNA and positive in the comparative method. When these samples were tested by a referee method one was negative and one was positive.

B. Linearity

Figures 1 and 2 show typical examples of the Is-dsDNA linearity. These figures depict the inhouse reference standard (which has been standardized against the Wo/80 Standard) tested by the Is-dsDNA after serial two-fold manual dilution in Sample Diluent. Separate dilutions were tested both manually and with MAGO. The results demonstrate a high degree of linearity for the Is-dsDNA Test Kit throughout the reportable range of the assay.

Image /page/2/Figure/10 description: The image contains two scatter plots comparing manual linearity and MAGO linearity. Both plots show the relationship between dilution and absorbance. The R-squared value for manual linearity is 0.9821, while the R-squared value for MAGO linearity is 0.9961, indicating a slightly better fit for the MAGO linearity data.

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C. Precision

The precision of the Is-dsDNA test kit was determined by testing six different sera and the kit calibrator and controls in triplicate in two runs on three different days. Precision was evaluated both manually and using the MAGO. The intra-and interassay precision is shown in Tables 2 and 3.

(AD)	BL	1	C
------	----	---	---

Is-dsDNA Precision (Manual)

Intra-assay *			Interassay **
	Day 1	Day 2	Day 3
SERUM	Mean SD %CV	Mean SD %CV	Mean SD %CV	Mean SD %CV
A (Neg)	7.8 1.6 N/A	6.7 0.7 N/A	7.4 0.9 N/A	7.3 1.2 N/A
B (Neg)	6.0 0.9 N/A	4.9 0.2 N/A	5.5 0.3 N/A	5.5 0.7 N/A
C (Pos)	78.2 10.1 12.9	71.1 5.0 7.0	75.0 2.7 3.6	74.8 7.0 9.3
D (Pos)	114.4 10.3 9.0	107.9 9.8 9.0	122.9 11.2 9.1	115.1 11.7 10.2
E (Pos)	202.8 16.2 8.0	199.0 27.7 13.9	232.3 27.3 11.7	211.4 27.5 13.0
F (Pos)	364.2 26.0 7.1	336.3 10.5 3.1	376.6 17.0 4.5	359.1 24.9 6.9
Cal.	372.9 26.1 7.0	346.0 37.4 10.8	384.1 20.4 5.3	367.7 31.7 8.6
Pos.	79.0 4.1 5.2	75.2 5.7 7.6	82.9 4.4 5.4	79.1 5.6 7.0
Neg.	7.1 2.1 N/A	5.6 1.3 N/A	5.7 1.4 N/A	6.1 1.7 N/A

		ls-dsDNA Precision (MAGO)


Intra-assay *						Interassay **
	Day 1			Day 2			Day 3
SERUM	Mean	SD	%CV	Mean	SD	%CV	Mean	SD	%CV	Mean	SD	%CV
A (Neg)	8.9	3.7	N/A	5.5	4.1	N/A	18.5	8.0	N/A	11.0	7.7	N/A
B (Neg)	9.0	1.9	N/A	6.6	4.4	N/A	9.4	2.1	N/A	8.3	3.1	N/A
C (Pos)	81.7	8.5	10.4	78.8	11.7	14.9	85.3	12.3	14.4	81.9	10.7	13.1
D (Pos)	114.7	13.5	11.8	102.6	13.4	13.0	112.8	18.7	16.6	110.0	15.5	14.1
E (Pos)	249.9	34.7	13.9	280.1	42.4	15.1	285.7	40.0	14.0	271.9	40.2	14.8
F (Pos)	360.3	12.6	3.5	366.5	15.0	4.1	398.0	20.8	5.2	374.9	23.0	6.1
Cal.	373.4	20.9	5.6	390.6	26.5	6.8	391.7	28.5	7.3	385.2	25.4	6.6
Pos.	100.1	15.6	15.6	102.3	10.4	10.1	104.2	7.8	7.5	102.2	11.2	11.0
Neg.	17.5	7.2	N/A	13.2	5.5	N/A	23.4	12.5	N/A	18.0	9.4	N/A
* n = 6				** n = 18

D. Crossreactivity

The absence of cross-reactivity in the Is-dsDNA was established by testing several sera (samples 1 to 11) containing some type of autoantibody by other methods, but with no antibody to ds DNA by other methods. These results are shown in Table 4.

Sample #	Is-dsDNA	Interp	Specificity
	IU/ml
1	7.7	NEG	SSA, SSB
2	9.3	NEG	SSA, SSB, Sm/RNP
3	14.1	NEG	Sm/RNP
4	4.1	NEG	Jo-1
5	9.1	NEG	Jo-1
6	12.3	NEG	Scl-70
7	22.2	NEG	Scl-70
8	4.1	NEG	SSA, Sm/RNP
9	15.3	NEG	SSA, SSB
10	11.7	NEG	Sm, Sm/RNP
11	18.9	NEG	Sm, Sm/RNP

TABLE 4

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In addition to the samples listed in Table 4, 49 samples containing varying levels of single-stranded DNA were also tested in the Is-dsDNA test Kit. Thirty seven samples were negative, one sample was borderline and eleven samples were positive. All eleven positive samples were also positive by at least two other commercially available tests for detecting dsDNA antibodies which would indicate that these samples indeed contain both ssDNA and dsDNA.

E. Expected Values

Antibodies to dsDNA are found in 60-70% of patients with SLE and are rarely present in normal populations. The expected values in the normal population were evaluated by assaying 200 normal donor sera collected in South Florida. Figures 3 and 5 show the distribution of dsDNA results in the normal population performed manually and on MAGO respectively. The distribution of IU/ml values for 50 sera from SLE patients is shown in Figures 4 and 6 performed manually and on MAGO respectively.

Image /page/4/Figure/3 description: The image contains four figures, each displaying a graph. Figures 3 and 4 are labeled "MANUAL," while Figures 5 and 6 are labeled "MAGO." Figures 3 and 5 are titled "Normals," and Figures 4 and 6 are titled "SLE patients." Each graph plots data points with "Number of Sera" on the x-axis and "IU/ml" on the y-axis, showing different distributions for normals and SLE patients under both MANUAL and MAGO conditions.

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F. Correlation of Manual and Mago Results

. .

V OCT Cateles of the MAGO IU/ml values for 249 samples tested in the Is-dsDNA Test Kit is shown in Figure 7.

Image /page/5/Figure/2 description: This image is a scatter plot showing the relationship between two variables. The y-axis is labeled "MAGO (IU/ml)" and ranges from 0 to 600. The data points are clustered near the origin and then spread out along a positive trend line. The R-squared value is 0.9334, indicating a strong positive correlation.

Image /page/5/Figure/6 description: The image shows the words "FIGURE 7" in bold, black font. The text is arranged on a single line, with "FIGURE" preceding the number "7". The image appears to be a label or title for a figure in a document.

Manual (IUml)

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Image /page/6/Picture/1 description: The image shows the logo for the U.S. Department of Health and Human Services. The logo consists of a stylized depiction of an eagle with its wings spread, positioned to the right of the department's name. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is arranged in a circular fashion around the eagle symbol.

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Lynne Stirling, Ph.D. Vice President, Regulatory Affairs MAR - 3 1998 Diamedix Corporation 2140 N. Miami Avenue Miami, Florida 33127

Re : K974694 Is-dsDNA Test System Trade Name: Regulatory Class: II Product Code: LRM Dated: December 15, 1997 December 16, 1997 Received:

Dear Dr. Stirling:

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 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, labelinq, and prohibitions aqainst misbranding and adulteration.

If your device is classified (see above) into either class II (Smecial Controls) or class III (Premarket Approval), it may be subject to such additional controls. Existing major requlations 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 requirement, as set forth in the Quality System Regulation (QS) for Medical Devices: General requlation (21 CFR Part 820) and that, through periodic (QS) 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 Requlations.

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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__________________________________________________________________________________________________________________________________________________________________________

510(k) Number (if known):_K97 4694

Device Name:

Indications For Use:

(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)

Concurrence of CDRH, Office of Defice Evaluation (ODE)

_
(Division Sign-Off)

Division of Clinical Laboratory Devices
510(k) Number K674694

Prescription Use
(Per 21 CFR 801.109)

Over-The-Counter Use__________________________________________________________________________________________________________________________________________________________

(Optional Format 1-2-96)

Regulation Number and Section

§ 866.5100 Antinuclear antibody immunological test system.

(a)
Identification. An antinuclear antibody immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the autoimmune antibodies in serum, other body fluids, and tissues that react with cellular nuclear constituents (molecules present in the nucleus of a cell, such as ribonucleic acid, deoxyribonucleic acid, or nuclear proteins). The measurements aid in the diagnosis of systemic lupus erythematosus (a multisystem autoimmune disease in which antibodies attack the victim's own tissues), hepatitis (a liver disease), rheumatoid arthritis, Sjögren's syndrome (arthritis with inflammation of the eye, eyelid, and salivary glands), and systemic sclerosis (chronic hardening and shrinking of many body tissues).(b)
Classification. Class II (performance standards).