Procedures for setting normal values

"Normal values" occupy an important place in medical practice. The judgment regarding the presence or absence of disease and the need to perform further testing or to treat may depend importantly on whether measured patient characteristics are within "normal limits". The types of measurements that may be of interest cover a broad spectrum, including most medical and laboratory assessments. Frequently, however, the quality of the available reference values are far from ideal, mainly because of unrepresentative selection of healthy subjects, inadequate sample size, lack of medical evaluation of subjects, failure to also measure other variables that influence the attribute studied, and failure to rigorously apply appropriate statistical analysis. Developing better normal values might result in more sensitive (detection of disease when it is present) and specific (not detecting disease when it is absent) identification of disease. Having better reference values even for such established tests as nerve conductions might result in tangible improvements in the value of the test. The approaches we will describe might also serve to create quality reference values for newly introduced measured phenomena and tests to be used in medical practice, epidemiologic research, and controlled clinical trials. In the following sections, we discuss clinical characteristics and laboratory measurements for which normal values might be needed, why a representative sample of subjects from a population is best, the deletions from this cohort that should be considered, additional variables that might also be assessed, and the specific statistical steps used to estimate variable-specific percentile values. This article is fashioned as a didactic guide. The insights are intuitive or practical extensions from consideration of scientific and statistical concepts. We provide a short list of references for background reading [1-15] and cite specific additional studies related to the examples we include. Tests and clinical phenomena for which reference limits can …

[1]  L. Elveback,et al.  STATISTICAL METHODS OF ESTIMATING PERCENTILES , 1969 .

[2]  R. Gräsbeck,et al.  Recommendations concerning the collection of reference values in clinical chemistry and activity report by the Committee on Reference Values of the Scandinavian Society for Clinical Chemistry and Clinical Physiology. , 1975, Scandinavian journal of clinical and laboratory investigation. Supplementum.

[3]  R. Penn,et al.  Neurosurgical horizons in Parkinson's disease , 1993, Neurology.

[4]  A. J. Schneider.  Some thoughts on normal, or standard, values in clinical medicine. , 1960, Pediatrics.

[5]  J. Albers,et al.  Plasma exchange in chronic inflammatory demyelinating polyradiculoneuropathy , 1985, Muscle & nerve.

[6]  P. Winkel,et al.  The normal region--a multivariate problem. , 1972, Scandinavian journal of clinical and laboratory investigation.

[7]  L. Wilkins.  Quantitative sensory testing , 1993, Neurology.

[8]  L. Elveback,et al.  Health, normality, and the ghost of Gauss. , 1970, JAMA.

[9]  Brain.  Aids to the Examination of the Peripheral Nervous System , 1987 .

[10]  P. Dyck,et al.  Human diabetic endoneurial sorbitol, fructose, and myo‐inositol related to sural nerve morphometry , 1980, Annals of neurology.

[11]  Mitchem Jc.  The use of mercury in dentistry. , 1989 .

[12]  J. Sninsky,et al.  Evaluation of screened blood donations for human immunodeficiency virus type 1 infection by culture and DNA amplification of pooled cells. , 1991, The New England journal of medicine.

[13]  J. Kurtzke.  A New Scale for Evaluating Disability in Multiple Sclerosis , 1955, Neurology.

[14]  J. Kurtzke,et al.  On the evaluation of disability in multiple sclerosis , 1961, Neurology.

[15]  R. Gräsbeck,et al.  Vitamin B12-binding proteins in human gastric mucosa. General pattern and demonstration of intrinsic factor isoproteins typical of mucosa. , 1975, Scandinavian journal of clinical and laboratory investigation.

[16]  P. Dyck,et al.  Neuropathy Symptom Profile in health, motor neuron disease, diabetic neuropathy, and amyloidosis , 1986, Neurology.

[17]  J. Kurtzke.  Rating neurologic impairment in multiple sclerosis , 1983, Neurology.

[18]  T. Scott.  Neurosarcoidosis , 1993, Neurology.

[19]  W. J. Litchy,et al.  The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population‐based cohort , 1993, Neurology.

[20]  J. Ebersole,et al.  An evaluation of ambulatory, cassette EEG monitoring , 1983, Neurology.

[21]  E. Sasse.  Determination of reference intervals in the clinical laboratory using the proposed guideline National Committee for Clinical Laboratory Standards C28-P. , 1992, Archives of pathology & laboratory medicine.

[22]  R. Gräsbeck,et al.  Theory of Reference Values , 1973 .

[23]  R. L. Rogers,et al.  Decreased cerebral blood flow precedes multi‐infarct dementia, but follows senile dementia of Alzheimer type , 1986, Neurology.

[24]  R. Dybkaer,et al.  Relative reference values for clinical chemical and haematological quantities in 'healthy' elderly people. , 2009, Acta medica Scandinavica.

[25]  A. Windebank,et al.  Plasma exchange in polyneuropathy associated with monoclonal gammopathy of undetermined significance. , 1991, The New England journal of medicine.

[26]  P. O'Brien,et al.  Statistical analysis in clinical laboratory medicine: fundamentals and common uses. , 1989, Critical reviews in clinical laboratory sciences.

[27]  M. F. Massod.  Nonparametric percentile estimate of clinical normal ranges. , 1977, The American journal of medical technology.

[28]  J. Lott,et al.  Estimation of reference ranges: how many subjects are needed? , 1992, Clinical chemistry.