February 2010 Clinical Laboratory News: Diagnostic Profiles

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February 2010: Volume 36, Number 2

PSA Velocity Found to have Little Value in Cancer Detection, Biopsy Decisions

The authors of a new study examining the clinical utility of prostate-specific antigen velocity (PSAV) for the early detection of prostate cancer conclude that there is “little evidence” that PSAV can enhance cancer detection in men with elevated PSA (European Urology 2009;56:753–760). Furthermore, the investigators “see little justification for formal calculation of PSAV and subsequent incorporation into a statistical model, and no justification for PSAV cut points, in determining indication for biopsy.” In light of their findings, the authors also suggest that existing guidelines on the use of PSAV to guide biopsy should be revised.

The researchers initiated their investigation after conducting a systematic review of PSAV following prostate cancer diagnosis, and discovering that there was little direct evidence that PSAV could help predict biopsy outcome. Their study involved a subgroup of 2,742 screening arm participants from the European Randomized Study of Screening for Prostate Cancer (ERSPC), a trial involving 182,000 subjects in seven European countries. All the participants had an elevated PSA ≥3 ng/mL and had a biopsy following subsequent biennial screens, but not after their baseline PSA test. Measurements of total, free, intact PSA and human kallikrein-related peptidase 2 (hK2) also were evaluated in relation to changes in PSAV.

PSAV was associated with small enhancements in predictive accuracy, with AUC of 0.569 versus 0.531, and 0.626 versus 0.609 when % fPSA was included. This relationship was not evident in men with high-grade disease. The predicted probability of prostate cancer with increasing PSAV peaked at 0.5 ng/mL, and declined below and above that point. In decision curve analyses showing the clinical benefit of basing biopsy decisions on various models of PSAV with other variables, PSAV provided clinical benefit only to a small number of men with high PSAV >0.75 ng/mL per year. According to the authors, this finding suggests that formally calculating PSAV and incorporating it in a multivariate model may be unnecessary. Instead, an informal assessment of PSAV will likely be of more value, such as evaluating men with a sudden rise in PSA levels for prostatitis before performing biopsy.

Testing Ranks High in Source of Diagnostic Errors

A recent report of the Diagnostic Error Evaluation and Research (DEER) project found that lab and radiologic testing had the greatest number of reported errors in the overall diagnostic process (Arch Intern Med 2009;169:1881–1887). DEER is a multi-year patient safety grant funded by the Agency for Healthcare Research and Quality, and the study was the largest reported case series of diagnostic errors to date, according to the researchers.

The investigators surveyed physician-respondents via anonymous written surveys during 20 grand ground sessions and by mail at two collaborating institutions. In all, there were 583 case reports of diagnostic error, an average of 2.2 per respondent. The most frequently missed diagnoses included pulmonary embolism, drug reaction or overdose, lung, colorectal and breast cancer, and acute coronary syndrome. In the category of lab or radiology tests, failure to order or a delay in ordering needed tests was the most common source of error, followed by erroneous lab or radiology reading of the test, failed or delayed reporting of results to the clinician, and technical errors or poor processing of the specimen or test.

While the study had limitations such as recall bias, it pointed out the overlapping and clustering of certain patterns of errors while enabling the researchers to identify generic factors that contribute to diagnostic errors. The analysis also highlighted the complexities behind diagnostic errors, including mingling between cognitive and system errors.

Subclinical Hypothyroidism Associated with Slight Mobility Advantage in the Elderly

A recent analysis of generally well-functioning seniors in their 70s found that individuals with mild subclinical hypothyroidism had a slight mobility advantage over their euthyroid counterparts (Arch Intern Med 2009;169:2011–17). After 2 years, even though there was a uniform decline in mobility across categories of thyroid function, subjects with subclinical hypothyroidism retained a slight functional advantage.

The researchers evaluated functional mobility because it is generally regarded as a global marker of current health status and risk of future negative health events in the elderly. The question was of interest because subclinical hypothyroidism has been associated with risk of numerous negative health outcomes, but evidence has been inconsistent, particularly in the elderly.

The investigators defined subclinical hypothyroidism as elevated thyrotropin (TSH) with normal levels of free thyroxine (FT4), in keeping with U.S. Preventive Service Task Force definitions. Subjects were assigned to three categories according to baseline TSH levels, including euthyroid (≥0.4 to <4.5 mIU/L) mild subclinical hypothyroid (≥4.5 to <7 mIU/L), and moderate subclinical hypothyroid (≥7 to ≤20 mIU/L). In addition to baseline TSH and FT4 measurements, participants underwent baseline and 2-year assessments of mobility based on usual and rapid gait speed and endurance walking ability.

The study did not attempt to address whether mildly elevated TSH levels contribute directly to higher functional mobility or whether they reflect some underlying physiologic adaption that promotes better health. The researchers called for further investigation into the meaning and any benefits of age-related increases in TSH levels.

Higher Urate Concentration Linked to Slower Progression of Parkinson Disease

New research indicates that higher serum and cerebrospinal fluid (CSF) urate levels are associated with slower rates of clinical decline in Parkinson disease (PD) (Arch Neurol, 2009;66:1460–68). The findings, which correlate closely with another recent study, “establish urate as the first molecular predictor of clinical progression in PD and provide a rationale for investigating the possibility that a therapeutic increase of urate in patients with PD might act favorably to slow the disease course,” according to the authors.

The study involved 800 subjects with early PD in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial, a 2-year study that explored the effects of deprenyl and α-tocopherol in delaying clinical decline in PD. The investigators found an inverse relationship between both serum and CSF urate concentrations and progression to DATATOP’s primary endpoint, clinical disability requiring levodopa therapy. The hazard ratios for reaching the primary endpoint were 36% and 35% lower among participants in the highest quintile versus lowest quintile of serum and CSF urate concentrations, respectively. These associations were present only among subjects who were not treated with α-tocopherol, an unexpected and unexplained outcome.

Since urate is an antioxidant and oxidative damage is thought to contribute to the neurodegenerative process in PD, the findings suggest a possible therapeutic role for elevating serum urate concentration, either through diet or drugs. However, this potential benefit would need to be weighed against possible adverse effects of such therapy. The study does not provide enough data to warrant a recommendation for or against urate therapy, according to the researchers.

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