## Reference ranges, prediction intervals [GxP / QC / QA]

Hi all,

pardon me if this is the wrong category. Not sure where else to put it?!?

I am reading up on prediction intervals.
Wikipedia is a good place to start for someone like me. Mainly because I know nothing and am uncritical of most new things.

Wikipedia says: "Prediction intervals are commonly used as definitions of reference ranges, such as reference ranges for blood tests to give an idea of whether a blood test is normal or not. For this purpose, the most commonly used prediction interval is the 95% prediction interval, and a reference range based on it can be called a standard reference range."

I find that very interesting and the idea is appealing and intuitive: We have n observations from a group of people we think are normal. We define the reference range form them. Then we sample the next subjects and checks if they are within the interval of observations defining normal ("standard"), too. And so forth. That interval defining normal builds the sample mean and a sampling variance from the normal ones into the prediction. Sounds right. At least to me when I read it. To you, too?

I have been an auditor and inspector doing work at various path labs for BE on four continents. When I ask to see how they define the reference ranges, the story is often that CROs or path labs sample some subjects and take the 2.5th percentile and the 97.5th percentile to define reference ranges*. I have generally accepted that. I have generally accepted anything as long as the CRO or path lab has given the ref. range some consideration.

Thinking very hard about it I have not ever seen any CRO use the prediction interval approach to define ref. ranges. Should they? What is your opinion here? Have you seen the approach with prediction intervals in use in any operations relating to BE?

Educate me, please. Thank you.

*: the exception is hemoglobin and hematocrit. After WHO published their rule about aberrant hemoglobin a few years back, some CROs revised their reference ranges in funny ways so that anyone on the brink of keeling over due to anemia could still be enrolled. Or they revised their SOPs on ways PI's or delegates could clear such subjects for participation. But I digress, this latter aspect is more a question of low ethical standards than a question of reference ranges. OK, I will take a deep inhalation from the Schütozomycin bong now, I promise to be calm the rest of the day.

I could be wrong, but...

Best regards,
ElMaestro

No, of course you do not need to audit your CRO if it was inspected in 1968 by the agency of Crabongostan.