In a reference sample of hundreds of healthy subjects, the laboratory reference range for a novel marker of cardiac injury is 0.04-0.08 U/mL at the standard 95% level of probability. The marker has very high sensitivity and specificity for myocardial tissue. The clinical cardiology team would like to use a 99.7% reference range to assess patients who come to the emergency department with chest pain and have a high pretest probability of cardiac ischemia. An elevated value of the marker is defined as exceeding the 99.7th percentile of the reference sample. Assuming a normal (Gaussian) distribution with a mean of 0.06 U/mL, which of the following most closely approximates the corresponding reference range?

Question

In a reference sample of hundreds of healthy subjects, the laboratory reference range for a novel marker of cardiac injury is 0.04-0.08 U/mL at the standard 95% level of probability.  The marker has very high sensitivity and specificity for myocardial tissue.  The clinical cardiology team would like to use a 99.7% reference range to assess patients who come to the emergency department with chest pain and have a high pretest probability of cardiac ischemia.  An elevated value of the marker is defined as exceeding the 99.7th percentile of the reference sample.  Assuming a normal (Gaussian) distribution with a mean of 0.06 U/mL, which of the following most closely approximates the corresponding reference range?

Quizplus · Accepted Answer

11ec160b_3718_6696_9249_6fc997cf5334_MD0001_00 A normal (Gaussian) distribution refers to a symmetrical, bell-shaped distribution with a fixed proportion of observations lying within a certain distance of the mean. This distance is called the standard deviation (SD) and reflects the degree of dispersion from the mean. According to the properties of this distribution, 68% of observations lie within 1 SD from the mean, with half (ie, 68/2 = 34%) above and half (34%) below the mean. The remaining 32% (= 100% − 68%) lie outside 1 SD from the mean, with half (ie, 32/2 = 16%) above and the other half (16%) below 1 SD from the mean. In addition, 95% of all observations lie within 2 SD of the mean, and 99.7% of all observations lie within 3 SD from the mean. This is the 68-95-99.7 rule. The 95% range for this marker with a mean of 0.06 U/mL is 0.04 to 0.08 U/mL; given a normal distribution, this represents the range given by mean ± 2 SD. Therefore, 1 SD = 0.01 (because 0.04 = mean − 2 SD = 0.06 − 2 SD = 0.06 − 2 × 0.01 and, similarly, 0.08 = 0.06 + 2 × 0.01). The 99.7% range is given by mean ± 3 SD; therefore, the 99.7% range is 0.03 (= mean − 3 SD = 0.06 − 3 × 0.01) to 0.09 (= mean + 3 SD = 0.06 + 3 × 0.01). Any result that falls outside this range (eg, a value exceeding this range) indicates that the value is different from what is seen in 99.7% of the reference population. In laboratory measurements, although 95% is often used as a reference range, a 99% range is used in certain cases (eg, to determine cutoff for troponin in acute myocardial infarction). Other laboratory analysis methods involve performing more specific calculations when it is important to detect a difference in one direction (eg, for a cancer marker, knowing that the value is significantly higher than normal is more important than knowing that it is significantly different-either higher or lower-than normal). In some cases, high-sensitivity assays (eg, high-sensitivity C-reactive protein testing) allow the detection of values in the lower range of normal, which would not have been possible with standard assays. Educational objective: In a normal (bell-shaped) distribution, 68% of all values are within 1 standard deviation (SD) from the mean; 95% are within 2 SD from the mean; and 99.7% are within 3 SD from the mean. __________ References: Statistical distributions commonly used in measurement uncertainty in laboratory medicine. (http://www.ncbi.nlm.nih.gov/pubmed/32063728) Targeting residual inflammatory risk: a shifting paradigm for atherosclerotic disease. (http://www.ncbi.nlm.nih.gov/pubmed/30873416)

In a Reference Sample of Hundreds of Healthy Subjects, the Laboratory