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Polymerase Chain Reaction for the Diagnosis of HIV Infection in Adults: A Meta-Analysis with Recommendations for Clinical Practice and Study Design

Douglas K. Owens, MD, MSc; Mark Holodniy, MD; Alan M. Garber, MD, PhD; John Scott, BA; Seema Sonnad, MS; Lincoln Moses, PhD; Bruce Kinosian, MD; and J. Sanford Schwartz, MD
[+] Article and Author Information

From Veterans Affairs Palo Alto Health Care System, Palo Alto, California; Stanford University, Stanford, California; and Department of Veterans Affairs Medical Center and University of Pennsylvania, Philadelphia, Pennsylvania. Acknowledgments: The authors thank Michael Newman for expert assistance with computer-based literature searches; Daniel Kent, MD, for assistance with the development of the quality scoring system; Andrea Sullivan for help with data analysis; and Lyn Dupre for helpful comments. Some of the methods used in this research are based on work sponsored by the John A. Hartford Foundation. Grant Support: In part by the Veterans Affairs Office of Research and Development, Health Services Research and Development Service (IIR #91-044.A); the Center for Health Care Evaluation (Health Services Research and Development Field Program, Veterans Affairs Health Care System, Palo Alto, California); and grant AI 27762-04 from the National Institutes of Health. Drs. Owens and Garber are supported by Veterans Affairs Health Services Research and Development Career Development Awards. Requests for Reprints: Douglas K. Owens, MD, MSc, Section of General Internal Medicine (111A), Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304. Current Author Addresses: Drs. Owens and Garber: Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue (111A), Palo Alto, CA 94304.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1996;124(9):803-815. doi:10.7326/0003-4819-124-9-199605010-00004
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Purpose: To do a meta-analysis of studies that have evaluated the sensitivity and specificity of polymerase chain reaction (PCR) assay for the diagnosis of human immunodeficiency virus (HIV) infection in adults. Evaluating the performance of PCR is difficult because in certain clinical situations, the sensitivity or specificity of PCR may exceed those of the current reference standard tests [enzyme immunoassay followed by confirmatory Western blot analysis]. Therefore, an additional goal was to develop recommendations for 1) the design of future evaluative studies of PCR and 2) the use of PCR in persons with suspected HIV infection.

Data Sources: Studies published between 1988 and 1994 that were identified in a search of 17 computer databases, including MEDLINE, and abstracts identified from conference proceedings.

Study Selection: Studies were included if DNA amplification by PCR was done on peripheral blood mononuclear cells from adults. Ninety-six studies met the inclusion criteria.

Data Extraction: Data were extracted independently by two reviewers. Study design was assessed independently by two investigators blinded to study results.

Results: Reported sensitivities for PCR range from 10% to 100%, and specificities range from 40% to 100%. A summary receiver-operating characteristic curve based on all 96 studies has a maximum joint sensitivity and specificity [upper left point on the curve, where sensitivity equals specificity] of 97.0% to 98.1%. If the threshold value that defines a positive PCR result is chosen so that sensitivity is higher than 98.1%, specificity will decrease to less than 98.1%. Conversely, if the threshold value that defines a positive PCR result is chosen so that specificity is greater than 98.1%, sensitivity will decrease to less than 98.1%. If sensitivity and specificity are chosen to be equal, the corresponding false-positive rate is 1.9% to 3.0%. At the maximum joint sensitivity and specificity, the positive predictive value of PCR ranges from 34% to 85% as the prevalence of HIV increases from 1.0% to 10%. We identified seven areas in which study design could be modified to 1) reduce susceptibility to bias in estimates of the sensitivity and specificity of PCR and 2) to increase the generalizability of the study results. These modifications will also help to overcome methodologic problems created by the lack of a reference standard test.

Conclusions: The PCR assay is not sufficiently accurate to be used for the diagnosis of HIV infection without confirmation. Use of PCR for the diagnosis of HIV in adults should be limited to situations in which antibody tests are known to be insufficient. Future studies of PCR performance should be sufficiently large and should use adequate reference standard tests and standardized methods for the performance of PCR. Specimens should be evaluated by persons blinded to clinical status and to the results of other diagnostic tests for HIV infection.

Figures

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Figure 1.
Calculated sensitivity and false-positive rate (1.0 − specificity) for included studies published before 1992.

Black squares indicate the sensitivity or false-positive rate; horizontal bars indicate the 95% Cls. A perfect test would have a sensitivity of 1.0 and a false-positive rate of 0.0 (specificity of 1.0). The reference number for each study is shown.

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Figure 2.
Results of quality ratings for individual quality criteria.Table 1

The number of studies that satisfied, partly satisfied, or failed to satisfy each criterion is shown. For an explanation of the scoring system for each criterion, see .

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Figure 3.
Summary receiver-operating characteristic curve for polymerase chain reaction (PCR).

The upper left corner of the summary receiver-operating characteristic (ROC) curve is shown. The summary ROC curve is based on all 96 included studies. The lower estimate (thin line) was calculated by including indeterminate PCR test results to determine a conservative estimate for sensitivity and specificity. The upper estimate (thick line) was calculated by excluding indeterminate PCR test results. The intersection of the diagonal line with each curve represents the maximum joint sensitivity and specificity for that ROC curve, where sensitivity equals specificity.

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Figure 4.
Post-test probability of human immunodeficiency virus (HIV) infection.

Upper curves show the post-test probability of HIV infection after a positive t polymerase chain reaction (PCR test result). Lower curves show the post-test probability of HIV infection after a negative PCR test result. It is assumed that PCR has a joint sensitivity and specificity between 97.0 (thin curves) and 98.1 (thick curves), consistent with the upper- and lower-estimate summary receiver-operating characteristic curve based on all 96 included studies.

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