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DOI: 10.1055/s-0038-1653746
Systematic Underestimation of Treatment Effects as a Result of Diagnostic Test Inaccuracy: Implications for the Interpretation and Design of Thromboprophylaxis Trials
Publication History
Received 17 May 1994
Accepted after resubmission 27 September 1994
Publication Date:
09 July 2018 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/199502/lookinside/thumbnails/10-1055-s-0038-1653746-1.jpg)
Summary
Many clinical trials that have assessed strategies for the prevention of deep vein thrombosis have employed diagnostic tests that are less accurate than venography. The correct interpretation of these trials has been the subject of considerable debate. This paper attempts to quantify the likely effects of the use of inaccurate diagnostic tests (in particular fibrinogen scanning) on the validity and precision of estimates of treatment effects. It is shown that, if there is no difference in the rate of misclassification of deep vein thrombosis between study and control groups, then treatment effects will tend to be systematically underestimated in trials that only use inaccurate diagnostic tests. However, for trials in which there are no false positive diagnoses, such as those employing venography, the estimate of relative treatment effects will be unbiased. This phenomenon is demonstrated empirically by data from randomised trials of antiplatelet therapy. The implications of these findings are two-fold. First, so long as the accuracy of the test is the same in study and control groups, positive trial results cannot be ascribed to diagnostic test inaccuracy. Second, unbiased estimates of relative treatment effects can be obtained by using cheap, practicable and non-invasive screening tests that are supplemented by venographic assessment of positive test results. This would facilitate the conduct of much larger randomised trials than has generally been possible when mandatory venography was used; if future trials randomised some thousands of patients and employed confirmatory venography then they would provide both unbiased and precise estimates of relative treatment effects.
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References
- 1 Heijboer H, ten Cate JW, Büller HR. Diagnosis of venous thrombosis. Semin Thromb Hemost 1991; 17 Suppl (Suppl. 03) 259-267
- 2 Lensing AW A, Prandoni P, Büller HR, Casara D, Cogo A, ten Cate JW. Lower extremity venography with iohexol: results and complications. Radiology 1990; 177: 503
- 3 Blumgart RL, Immelman EJ, Jeffery PC, Lipinski JK. Thrombotic side-effects of lower limb venography. The use of heparin-saline flush S Afr Med J 1991; 79: 88-89
- 4 Lensing AW A, Hirsh J. 125I-Fibrinogen leg scanning: reassessment of its role for the diagnosis of venous thrombosis in post-operative patients. Thromb Haemost 1993; 69 (01) 2-7
- 5 Wells P, Lensing AW A, Hirsh J. Graduated compression stockings in the prevention of postoperative venous thromboembolism. A meta-analysis Arch Intern Med 1994; 154: 67-72
- 6 Jørgensen LN, Wille-Jørgensen P, Hauch O. Prophylaxis of postoperative thromboembolism with low molecular weight heparins. Br J Surg 1993; 80: 689-704
- 7 Collins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. Overview of results of randomized trials in general, orthopaedic and urologic surgery NEJM 1988; 318: 1162-1172
- 8 Harris WH, Athanasoulis C, Waltman AC, Salzman EW. Cuff-impedance phlebography andl25I fibrinogen scanning versus roentgenogrpahic phlebography for diagnosis of thrombophlebitis following hip surgery. A preliminary report J Bone Joint Surg 1976; 58 A 939-944
- 9 Moskovitz PA, Ellenburg SS, Feffer HL, Kenmore PI, Neviaser RJ, Rubin BE, Varma VM. Low-dose heparin for prevention of venous thromboembolism in total hip arthroplasty and surgical repair of hip fractures. J Bone Joint Surg 1978; 60 A 1065-1070
- 10 Sautter RD, Koch EL, Myers WO, Ray JR, Mazza JJ, Larson DE, Chen HM, Milbauer JP, Treuhaft PS, Plotka ED, Wenzel FJ, Nycz G, Pierce WE. Aspirin-sulfinpyrazone in prophylaxis of deep venous thrombosis in total hip replacement. JAMA 1993; 250: 2649-2654
- 11 Cruickshank MK, Levine MN, Hirsh J, Turpie AG, Powers P, Jay R, Gent M. An evaluation of impedance plethysmography and l25I-fibrinogen leg scanning in patients following hip surgery. Thromb Haemost 1989; 62: 830-834
- 12 Hull RD, Raskob GE, Gent M, McLoughlin D, Julian D, Smith FC, Dale I, Reed-Davis R, Lofthouse RN, Anderson C. Effectiveness of intermittent pneumatic leg compression for preventing deep vein thrombosis after total hip replacement. JAMA 1990; 263: 2313-2317
- 13 Faunø P, Suomalainen O, Bergqvist D, Fredin H, Kettunen K, Soimakallio S, Cederholm C, Karjalainen P, Vissinger H, Justeson T. The use of the fibrinogen uptake test in screening for deep vein thrombosis in patients with hip fracture. Thrombosis Research 1990; 60: 185-190
- 14 Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy – III: Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. Br Med J 1994; 308: 235-246
- 15 Wacholder S, Lubin JH, Dosemeci M, Gail MH. Bias despite masked outcome assessment of clinical outcomes when an outcome is defined as one of several component events. Controlled Clinical Trials 1991; 12: 457-461
- 16 Rothman KJ. Modem epidemiology. Boston: Little Brown and Company; 1988
- 17 Hsieh C-C. The effect of non-differential outcome misclassification on estimates of the attributable and prevented fraction. Stat Med 1991; 10: 361-373
- 18 Copeland KT, Checkoway H, McMichael AJ, Holbrook RH. Bias due to misclassification in the estimation of relative risk. Am J Epid 1977; 105: 488-495