The origin of reference intervals: A college of American pathologists Q-probes study of "normal ranges" used in 163 clinical laboratories

Context. - Standards have been developed for establishing reference intervals, but little is known about how intervals are determined in practice, interlaboratory variation in intervals, or errors that occur while seifing reference intervals. Objectives. - To determine (1) methods used by clinical laboratories to establish reference intervals for 7 common analytes, (2) variation in intervals, and (3) factors that contribute to establishment of "outlier" intervals. Design. - One hundred sixty-three clinical laboratories provided information about their reference intervals for potassium, calcium, magnesium, thyroid-stimulating hormone, hemoglobin, platelet count, and activated partial thromboplastin time. Results. - Approximately half the laboratories reported conducting an internal study of healthy individuals to validate reference intervals for adults. Most laboratories relied on external sources to establish reference intervals for pediatric patients. There was slight variation in intervals used by the central 80% of study laboratories, but some laboratories outside the central 80% had surprisingly low and high limits for their reference intervals, in some cases the intervals used by 2 laboratories had no overlap. For example, one laboratory considered a hemoglobin of 13.8 g/dL in a woman to be "low" while another considered the same value to be "high". Three percent of reference intervals contained a limit that qualified as an "outlier" using standard statistical tests; we could not identify any practice associated with adoption of outlier intervals. Conclusions. - Many laboratories adopt reference intervals from manufacturers without on-site testing of healthy individuals. Reference intervals used by facilities that forgo on-site testing are not statistically different from intervals validated with on-site studies.