Development Of Reference Intervals Research Articles

SAT015 Improving The Quality Of Disease Biomarker Measurements In Patient Care And Research-CDC's Clinical Standardization Programs

Abstract Disclosure: O. Sugahara: None. T. Buchannan: None. U. Danilenko: None. A. Ribera: None. L. Collins: None. N. Vasquez: None. K. Dahya: None. F. Pokuah: None. H. Zhou: None. L. Zhang: None. A.N. Lyle: None. H.W. Vesper: None. High-quality disease biomarker tests are critical for the correct diagnosis and treatment of patients, accurate interpretation of research data, and effective use of research findings in health care. CDC’s Clinical Standardization Programs (CDC CSP) assist researchers and laboratories with assessing and improving the analytical performance of biomarker tests performed in patient care, public health, and research. CDC CSP develops and applies reference methods, materials, and protocols to consistently calibrate biomarker tests across instruments and laboratories and to assess and improve other analytical performance characteristics, such as analytical specificity. CDC CSP works with test manufacturers and laboratories operating in-house developed tests to correctly calibrate tests. Additional programs help clinical and research laboratories monitor the accuracy and reliability of tests over time. Furthermore, CDC CSP collaborates with researchers on the development of reference intervals and on using new and emerging biomarkers in patient care and public health. CDC CSP provides comprehensive programs for traditional blood lipids, testosterone, estradiol, vitamin D, and free thyroxine. Programs for free testosterone, parathyroid hormones, apolipoproteins, and angiotensin peptides will be available soon. CDC CSP collaborated with members of the Partnership for the Accurate Testing of Hormones (PATH) and established reference intervals for testosterone in men. CDC CSP is currently working to develop reference intervals for testosterone in women and for estradiol in postmenopausal women. A CDC CSP interlaboratory study on free thyroxine measurements showed high variability in calibration accuracy among free thyroxine assays. CDC CSP is using its reference methods and materials to minimize this variability. It is anticipated that assay recalibration may change measurement values for some tests by up to 50%. CDC CSP is working with PATH and the International Federation for Clinical Chemistry and Laboratory Medicine (IFCC) to educate stakeholders about the upcoming change in free thyroxine measurements. Presentation: Saturday, June 17, 2023

An unsupervised learning method to identify reference intervals from a clinical database

Reference intervals are critical for the interpretation of laboratory results. The development of reference intervals using traditional methods is time consuming and costly. An alternative approach, known as an a posteriori method, requires an expert to enumerate diagnoses and procedures that can affect the measurement of interest. We develop a method, LIMIT, to use laboratory test results from a clinical database to identify ICD9 codes that are associated with extreme laboratory results, thus automating the a posteriori method. LIMIT was developed using sodium serum levels, and validated using potassium serum levels, both tests for which harmonized reference intervals already exist. To test LIMIT, reference intervals for total hemoglobin in whole blood were learned, and were compared with the hemoglobin reference intervals found using an existing a posteriori approach. In addition, prescription of iron supplements were used to identify individuals whose hemoglobin levels were low enough for a clinician to choose to take action. This prescription data indicating clinical action was then used to estimate the validity of the hemoglobin reference interval sets. Results show that LIMIT produces usable reference intervals for sodium, potassium and hemoglobin laboratory tests. The hemoglobin intervals produced using the data driven approaches consistently had higher positive predictive value and specificity in predicting an iron supplement prescription than the existing intervals. LIMIT represents a fast and inexpensive solution for calculating reference intervals, and shows that it is possible to use laboratory results and coded diagnoses to learn laboratory test reference intervals from clinical data warehouses.

‘Aussie normals’: an a priori study to develop clinical chemistry reference intervals in a healthy Australian population

Development of reference intervals is difficult, time consuming, expensive and beyond the scope of most laboratories. The Aussie Normals study is a direct a priori study to determine reference intervals in healthy Australian adults. All volunteers completed a health and lifestyle questionnaire and exclusion was based on conditions such as pregnancy, diabetes, renal or cardiovascular disease. Up to 91 biochemical analyses were undertaken on a variety of analytical platforms using serum samples collected from 1856 volunteers. We report on our findings for 40 of these analytes and two calculated parameters performed on the Abbott ARCHITECTci8200/ci16200 analysers. Not all samples were analysed for all assays due to volume requirements or assay/instrument availability. Results with elevated interference indices and those deemed unsuitable after clinical evaluation were removed from the database. Reference intervals were partitioned based on the method of Harris and Boyd into three scenarios, combined gender, males and females and age and gender. We have performed a detailed reference interval study on a healthy Australian population considering the effects of sex, age and body mass. These reference intervals may be adapted to other manufacturer's analytical methods using method transference.

Use of cyst fluid CEA, CA19-9, and amylase for evaluation of pancreatic lesions

Objectives The study goals were development of reference intervals and an interpretive algorithm for pancreatic cyst fluid tumor markers. Design and methods 442 pancreatic cyst fluids were tested for CEA, CA19-9, and amylase. Results CEA > 30 ng/mL discriminates mucinous from non-mucinous cysts. After CEA analysis, amylase and CA19-9 segregate non-mucinous and mucinous subtypes, respectively. Conclusions Pancreatic cyst fluid tumor markers supplement other diagnostic measures. This study provides estimated reference intervals and an algorithm for interpretation.

Luteinizing Hormone and Follicle-Stimulating Hormone Levels in Extreme Prematurity: Development of Reference Intervals

Establishing pediatric reference intervals has always been challenging, with most ranges used in pediatric laboratories developed over many years. The clinical interpretation of gonadotropins is important in the context of ambiguous genitalia. The aim of this study was to develop reference intervals for luteinizing hormone and follicle-stimulating hormone in infants born between 24 and 29 weeks' gestation. Samples were collected at 0 to 43 days after birth from 82 premature infants born <30 weeks' gestation for analysis of luteinizing hormone and follicle-stimulating hormone by automated immunochemiluminometric immunoassays. The 43 male infants demonstrated a range of luteinizing hormone levels from 0.1 to 13.4 IU/L and of follicle-stimulating hormone levels from 0.3 to 4.6 IU/L. The 39 female infants demonstrated a range of luteinizing hormone levels from 0.2 to 54.4 IU/L and of follicle-stimulating hormone levels from 1.2 to 167.0 IU/L. The ratio of luteinizing hormone/follicle-stimulating hormone levels differed with males, ranging from 0.3 to 9.4, and females, at <0.5. These data provide guidance for the interpretation of luteinizing hormone and follicle-stimulating hormone levels for the first 6 weeks of life in extremely premature infants born between 24 and 29 weeks' gestation. The availability of age-appropriate reference intervals is essential for correct and timely interpretation of biochemical results to the clinician.