Olga Navolotskaia

Reference distributions for the negative acute-phase serum proteins, albumin, transferrin and transthyretin: A practical, simple and clinically relevant approach in a large cohort

Inflammation is associated with diverse clinical conditions accompanied by characteristic changes in serum levels of the acute‐phase proteins that can be used to stage the inflammatory process and evaluate the impact of treatment. Some acute‐phase proteins increase during inflammation, while others, such as albumin, transferrin, and transthyretin, decrease. The current study reports reference ranges for serum levels of albumin, transferrin, and transthyretin based on a cohort of over 124,000 Caucasian individuals from northern New England, tested in our laboratory between 1986 and 1998. Measurements were standardized against CRM 470 (RPPHS) and analyzed using a previously validated statistical approach. Individuals with laboratory evidence of inflammation (C‐reactive protein of 10 mg/L or higher) were excluded. The levels of all three analytes varied by age, generally rising until the second or third decade of life and then decreasing thereafter. Albumin and transthyretin levels were higher during midlife among males as compared to females; the maximum being at 25 years for albumin (5%) and 35 years for transthyretin (16%). In contrast, above the age of 10 years, transferrin levels were increasingly higher among females (7% at 20 years). When values were expressed as multiples of the age‐ and gender‐specific median levels, the resulting distributions fitted a log‐Gaussian distribution. When patient data are normalized in this manner, the distribution parameters can be used to assign a corresponding centile to an individuals measurement simplifying interpretation. The ultimate interpretation of an individuals measurement relies upon the clinical setting. J. Clin. Lab. Anal. 13:273–279, 1999.

Reference distributions for immunoglobulins A, G, and M: A practical, simple, and clinically relevant approach in a large cohort

Serum immunoglobulins are measured millions of times each year, yet clinical interpretations remain hampered by inadequate age‐ and gender‐specific reference limits. In order to provide more reliable and comprehensive reference distributions for IgA, IgG, and IgM measurements, we analyzed automated immunoassay values from 115,017 serum samples from northern New England patients (99% Caucasian) who were tested in our laboratory between 1986 and 1995. Measurements were standardized to reference material, CRM 470 (RPPHS). A simple, practical, and clinically relevant approach was used to determine reference distributions for the immunoglobulins over a wide range of ages for males and females. Levels of IgA and IgM varied considerably by age, and by gender for IgM. For each of the analytes, the observed 5th and 95th centiles were symmetric about the median and approximately constant over the entire age range. When immunoglobulin reference values are expressed as multiples of the age‐ and gender‐specific regressed medians, the resulting distributions fit a log‐Gaussian distribution well. This finding enables interpretation of serum immunoglobulin measurements using a common unit (multiples of the median) that is independent of age or gender. Insights gained from this study can help improve and simplify the interpretation of immunoglobulin measurements. J. Clin. Lab. Anal. 12:363–370, 1998.

Reference distributions for the positive acute phase serum proteins, ?1-acid glycoprotein (orosomucoid), ?1-antitrypsin, and haptoglobin: A practical, simple, and clinically relevant approach in a large cohort

Most clinical conditions are accompanied by corresponding changes in serum levels of some, if not all, of the acute phase proteins. While conditions that affect the acute phase proteins are usually inflammatory in nature, non‐inflammatory conditions also can cause changes (e.g., malnutrition, some malignancies without secondary inflammation, and genetic polymorphism). Only after the confounding effects of non‐inflammatory conditions are taken into account can these measurements be used to detect and stage the inflammatory process and to evaluate the impact of treatment. In this third article in a series, reference ranges for serum levels for three of the acute phase proteins that increase during inflammation are examined: α1‐acid glycoprotein (orosomucoid), α1‐antitrypsin, and haptoglobin. The study is based on a cohort of 55,199 Caucasian individuals from northern New England, tested in our laboratory between 1994 and 1999. Measurements were standardized against CRM 470 (RPPHS) and analyzed using a previously described statistical approach. Individuals with unequivocal laboratory evidence of inflammation (C‐reactive protein of 10 mg/l or higher) were excluded. Levels of α1‐acid glycoprotein changed little during life and between the sexes. Levels of α1‐antitrypsin varied somewhat by age, rising slightly beyond age 55; males followed a pattern similar to that for females. For this protein, it was necessary to apply two equations to describe the lower levels associated with certain phenotypes. Haptoglobin levels fell significantly during the first decade of life for both males and females and climbed thereafter. Males and females displayed a similar pattern. When values were expressed as multiples of the age‐ and gender‐specific median levels, the resulting distributions fitted a log–Gaussian distribution well over a broad range. When patient data are normalized in this manner, the distribution parameters can be used to assign a centile corresponding to an individual’s measurement, thus simplifying interpretation. J. Clin. Lab. Anal. 14:284–292, 2000.

REFERENCE DISTRIBUTIONS FOR IMMUNOGLOBULINS A, G, AND M : A COMPARISON OF A LARGE COHORT TO THE WORLD'S LITERATURE

Clinical interpretation of immunoglobulin measurements requires accurate and precise assays and widely accepted reference preparations, as well as reliable age‐ and gender‐specific reference ranges. This last requirement, the topic of numerous publications, has not been addressed adequately. By a combination of computerized and hand searching of the literature from 1961 to 1997, we identified 109 publications presenting IgA, IgG, and/or IgM reference data in healthy individuals. After eliminating studies that lacked appropriate clinical, statistical, or reference material information, data from the 17 acceptable studies were converted to a common reference material, CRM 470/RPPHS. When median levels from our recently published large cohort study are superimposed on these published medians, they fall within the ranges of reported medians. The widths of published 95 percentile reference ranges (where each individuals health was verified) were also found to agree closely with the reference range widths found in our data (where inclusion was based on the reported diagnosis). The current combined study of narrowly applied reference ranges validates our recently published age‐ and gender‐specific reference data for immunoglobulins A, G, and M. Those new data can now be considered as a source of reliable reference ranges to be used by laboratories when interpreting immunoglobulin measurements. J. Clin. Lab. Anal. 12:371–377, 1998.

Reference distributions for the positive acute phase proteins, α1‐acid glycoprotein (orosomucoid), α1‐antitrypsin, and haptoglobin: A comparison of a large cohort to the world’s literature

Limiting bedside use of positive acute phase protein measurements (α1‐acid glycoprotein (orosomucoid), α1‐antitrypsin, and haptoglobin) has been the lack of satisfactory methods for quantifying serum levels and a credible reference material. Great strides have been made in the last few years. The remaining barrier to more relevant and cost‐effective use of serum protein data for diagnosis and prognosis is the availability of reliable reference intervals from birth to old age for both males and females. Sixty publications reporting reference intervals have been identified which meet the criteria used in our prior two studies, and these have been analyzed statistically. Previous small studies of these individual proteins agree on average, over their constrained age ranges, with our life‐long reference ranges. This meta‐analysis provides support for our reference ranges and places them in the perspective of previous publications. J. Clin. Lab. Anal. 14:265–270, 2000.