The data warehouse as a foundation for population-based reference intervals

The volume of data contained in a data warehouse represents a potential resource to provide the basis for detailed and specific reference intervals. Routine chemistry panel testing data were derived from an outreach laboratory patient population of 438,180 people and then screened by multiple data filters to identify a large and demographically diverse reference population. Reference intervals were determined for 4 common analytes: aspartate aminotransferase, alanine aminotransferase, total bilirubin, and alkaline phosphatase. Each derived reference population contained more than 60,000 people with sex- and age-specific subgroups comprising between 495 and 4,949 persons. These intervals are particularly representative of the aging patient population and demonstrate a degree of age and sex diversity not reflected commonly in routine laboratory reference intervals. Warehouse data also can yield other interpretative data, such as percentile ranking of results or disease-specific reference intervals. As the warehouse accumulates data from other disciplines (such as from clinical notes or pharmacy), there is increasing potential for the laboratory to enhance the clinician's ability to diagnose and treat disease.     

国家行业标准ALT、AST、ALP、GGT参考区间的验证试验

目的 验证国产试剂ALT、AST、ALP、GGT的参考区间是否符合行业标准参考区间.方法 按照国家行业标准WS/T 404.1-2012《临床常用生化检验项目参考区间第1部分：血清丙氨酸氨基转移酶、天门冬氨酸氨基转移酶、碱性磷酸酶和γ-谷氨酰基转移酶》参考人群筛选标准,于2013年9月筛选北京九强生物技术股份有限公司20～62岁健康体检者107名,其中男35名,女72名,使用非参数统计方法统计本研究人群的参考区间,与行标参考区间进行比较.结果 使用金斯尔试剂ALT、AST、GGT、ALP得到的参考区间,与行业标准比较,基本一致.结论 临床医院使用金斯尔品牌试剂可以.直接使用新行业标准推荐的参考区间.     

Age-related reference intervals for free and total prostate-specific antigen in a Singaporean population

Cancer of the prostate is the sixth most frequently found cancer in Singapore. Prostate-specific antigen (PSA) is the most clinically useful tumour marker available today for the diagnosis and management of prostate cancer. To enhance the value of PSA as a screening test we developed age-specific intervals for our ethnic population. The measurement of free PSA was included in the study to calculate the free:total ratio which enhances the differential diagnosis of prostate cancer from benign prostatic hyperplasia or prostatitis. The total PSA upper limits of 10-year intervals, beginning at 30-years-old, were 1.4, 1.7, 2.3, 4.0, 6.3 and 6.6 microg/l. Free PSA cut-off limits were 0.4, 0.5, 0.5, 1.0, 1.5 and 1.6 microg/l. The free:total ratio of PSA was not age dependent. Abbott AxSym standardised their calibration material for both free and total PSA assays with the Stanford 90:10 reference material. This laboratory has implemented these age-specific reference intervals and are currently following up their pick-up rate in the detection of prostate cancer.     

Determination of reference ranges for serum enzymes via a large interlaboratory survey

We obtained enzyme data on normal individuals in conjunction with a large interlaboratory enzyme survey. For the 12 largest peer groups using unique methods, we found a simple relationship between the upper reference limits and the laboratories' results obtained from human-enzyme-supplemented survey serum. A conversion to a common base made possible the merging of data on the normal individuals and interconversion of results by diverse methods. We determined the upper reference limits for serum lactate dehydrogenase, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and creatine kinase for approximately 8000 adult men and women believed to be in good health. Using a technique described here, we believe that the results can be transformed to user-specific units, and that the large data base can be applied to the many diverse enzyme methods in current use. With these data, enzyme survey participants will be able to estimate appropriate reference intervals for their particular method.     

Clinical haematology of the southern brown bandicoot (Isoodon obesulus)

Haematological assessment may contribute in monitoring the health of wild animals. However, species-specific reference intervals are required for maximal information to be gained from any haematological assessment. The purpose of this study was to assess the haematological characteristics for a population of southern brown bandicoots (Isoodon obesulus), a small marsupial common, across southern Australia. Animals from a wild population (n=65) were sampled between March 2004 and February 2005. Blood from these animals was assessed by microscopy, manual techniques (packed cell volume, total solids, and fibrinogen) and using an automated haematology analyser. Southern brown bandicoots were found to have similar leukocytes and erythrocytes to those previously described for other species of bandicoots, and the measured values for the haematological analytes were similar to those previously published for the species. For most analytes there were no statistically significant differences observed between males and females, and lactating and non-lactating animals. The observed values for each of the analytes in the current study may be used to aid in the detection of disease and monitoring of health in wild and captive populations of bandicoots.     

The influences of sample distribution and age on reference intervals for adult males

This investigation was designed to improve reference information and to evaluate the influences of sample distribution and age on the derived reference intervals. Specimens from 127 men were collected after a 12- to 14-hour fast and analyzed by 60 different laboratory procedures. Differences in the reference intervals derived, using three separate statistical methods, appeared to be unimportant clinically, but the percentile method was preferred because it required no assumptions concerning the frequency distribution. Relationships between age and analyte concentrations were examined by linear regression analysis, and the analytes were placed in one of three groups, according to the significance of this relationship: greatest significance (P less than or equal to 0.01), 18 analytes; intermediate significance (0.01 less than or equal to P less than or equal to 0.05), 12 analytes; and least significance (P greater than 0.05), 30 analytes. The age-related changes for each analyte were evaluated according to analytic variation, population dispersion, and clinical relevance. Age-dependent reference intervals for adult males are recommended for albumin, cholesterol, phosphorus, and sedimentation rate.     

Influence of age and sex on the serum biochemical profile of Doberman dogs in the growth phase

The physiological variations and the influence of sex and age on the serum biochemical profile of dogs were evaluated based on an analysis of 132 blood specimens from 44 newly weaned and young adult Doberman dogs, ranging in age from 2 to 36 months, from a private kennel. The analyses were processed colorimetrically in an automatic analyzer using commercial kits. The mean values of the serum biochemical parameters analyzed here remained mostly within the physiological reference intervals. The only differences were albumin, which showed higher values and chloride with lower values than those reported in the literature, suggesting that the animals were in good health. The age brackets showed significant differences in serum concentrations of total protein, albumin, globulins, albumin/globulins (A/G) ratio, urea, creatinine, cholesterol, total calcium, ionized calcium, phosphorus, iron, alanine aminotransferase (ALT) and alkaline phosphatase (ALP). In terms of sex-related differences, phosphorus was higher in males and the calcium/phosphorus (Ca/P) ratio was higher in females. Age appeared to influence several serum biochemical parameters in young Doberman dogs, especially up to 6 months of age, while sex influenced only the serum phosphorus concentration and the Ca/P ratio.     

Height, weight, and body mass index among Akwesasne Mohawk youth.

Information on the growth of contemporary Native American adolescents is limited. A few studies have shown that Native Americans have growth patterns that may differ from U.S. reference values. We describe basic anthropometric characteristics (height and weight) of Mohawk youth between the ages of 10.0 and 16.99 years from the Akwesasne Mohawk Nation. Body mass index (BMI) was calculated. Mean height of Akwesasne Mohawk youth approximates the 50th percentile of reference values as determined by the 2000 Center for Disease Control and Prevention (CDC) growth charts. At every age, weight means of males approximate or exceed the 90th percentile and all mean weights of females approximate the 85th percentile. Akwesasne males are significantly taller than females from age 14 on and significantly heavier at ages 14 and 16. All age-specific BMI means for males are at or above the 90th percentile and females' means are at or above the 85th. The potential for long-term health effects associated with being overweight has implications for the future health of young Native Americans.     

Harmonization of practices: application to the measurement of enzymatic activities used in prevention, screening, diagnosis and therapeutic monitoring

The large metrological variation (CV, about 25%) observed between laboratories, at the national French level, for the measurement of enzymatic activities results in a loss of efficiency in using laboratory results. Current data show that the standardisation of methods is insufficient to solve this problem and needs to be completed by an harmonisation of the practices including the use of a common reference (calibrator). The present work, carried out by the joint working group between laboratories of the Centres for Periodic Health Examination and the French Society of Clinical Biology (SFBC), deals mainly with the feasibility and evaluation of the improvement of the consistency of the results. Twenty laboratories participated in this study. Five independent surveys were conducted during an height month period. Two enzymes were selected because of their clinical importance and their interest in prevention, screening, diagnosis or epidemiology: ALT (alanine aminotransferase) and GGT (gamma-glutamyltransferase). In each survey three kinds of samples i.e. control sera, candidate calibrators and human serum pools, each of them at two levels of activity (one physiological and the other pathological) were measured in duplicate. The low intra-laboratory imprecision and the high degree of the standardisation of used methods, due to an important effort previously done in this field, permitted to consider a common calibration. The stability and mainly the commutability, i.e. the ability for the candidate calibrator to show a behaviour similar to that of human samples towards the used methods, allowed to reduce the inter-laboratory variation by a half to two third-fold, reaching a coefficient of variation < 5% similar to those observed for cholesterolemia or glycemia. This level of consistency should permit to use common reference limits and common decision limits, after validation of this approach in real practice. The consequences of the harmonisation of practices, extended to the all laboratories, exceed largely the scope of this study. The reduction of the uncertainty and a better approach of the accuracy for the measurement of enzymatic activities should led to a real benefit for the patients in terms of prevention, screening, diagnosis or therapeutic monitoring and consequently for the public health.     

Pediatric laboratory medicine: current challenges and future opportunities

The practice of pediatric laboratory medicine involves unique challenges related to development, nutrition, growth, and diseases during different periods of infancy, childhood, and adolescence. This article discusses key aspects of pediatric laboratory medicine faced by clinical pathologists, clinical laboratory scientists, and clinicians, including point-of-care testing, preanalytic variables, analytic factors, age-specific reference intervals, esoteric laboratory tests, clinical impact, andfuture opportunities. Although challenging, pediatric laboratory testing offers many opportunities for improved patient care, clinical- and laboratory-based research, and education.     

Neurodevelopmental MRI brain templates for children from 2 weeks to 4 years of age

Spatial normalization and segmentation of pediatric brain magnetic resonance images (MRI) data with adult templates may impose biases and limitations in pediatric neuroimaging work. To remedy this issue, we created a single database made up of a series of pediatric, age-specific MRI average brain templates. These average, age-specific templates were constructed from brain scans of individual children obtained from two sources: (1) the NIH MRI Study of Normal Brain Development and (2) MRIs from University of South Carolina's McCausland Brain Imaging Center. Participants included young children enrolled at ages ranging from 8 days through 4.3 years of age. A total of 13 age group cohorts spanning the developmental progression from birth through 4.3 years of age were used to construct age-specific MRI brain templates (2 weeks, 3, 4.5, 6, 7.5, 9, 12, 15, 18 months, 2, 2.5, 3, 4 years). Widely used processing programs (FSL, SPM, and ANTS) extracted the brain and constructed average templates separately for 1.5T and 3T MRI volumes. The resulting age-specific, average templates showed clear changes in head and brain size across ages and between males and females, as well as changes in regional brain structural characteristics (e.g., myelin development). This average brain template database is available via our website (http://jerlab.psych.sc.edu/neurodevelopmentalmridatabase) for use by other researchers. Use of these age-specific, average pediatric brain templates by the research community will enhance our ability to gain a clearer understanding of the early postnatal development of the human brain in health and in disease.     

Reference change values of blood analytes from physically active subjects

The analysis of blood constituents allows the detection of various physiological or pathological states when their values are increased or decreased in relation to a well-defined reference group or to themselves if monitored longitudinally. In the latter case, it is important to know the reference change value (RCV) or critical difference, which defines the percentage change that should be exceeded—given the analytical and biological variations inherent to a particular test, in that there is a significant difference between the two consecutive measurements. Our objective was to calculate the biological variation, analytical variation and RCV of the biochemical and hematological parameters in subjects undergoing 4 months of regular aerobic training. Blood samples (10 mL) were collected monthly from 56 male subjects (17–19 years old). Creatine kinase and aspartate aminotransferase activities, total cholesterol, triglycerides, uric acid, C-reactive protein, alpha-1-acid glycoprotein, creatinine and urea concentrations were measured in sera using an Autolab Boehringer analyzer. Hemogram were obtained from total blood using KX-21 N SYSMEX^? equipment. The RCV values for leukocytes and all biochemical analytes were elevated compared to the literature values of sedentary subjects. On the other hand, the RCV values for red blood cell count were slightly lower in physically active than in sedentary individuals. Knowledge of analyte RCV values within physically active subjects should improve the sensitivity/specificity of the hematological and biochemical alterations induced by training or the use of recombinant form of erythropoietin through blood parameter analysis, particularly in cases of longitudinal monitoring.     

Determination and validation of reference intervals.

A brief overview of the concept of the reference interval and its application in medical practice is presented. The populations from whom it is possible to derive reference intervals are discussed. Procedures used to develop reference intervals from both a selected healthy population and from hospitalized patients are discussed, and the influence of statistical method on presented reference intervals is reviewed. However, the weakness of using a reference interval derived from a population of individuals to facilitate interpretation of test results is illustrated in relationship to the variability of test results within an individual. In spite of the efforts that are made within the clinical laboratory through development of reference intervals to provide maximum guidance to clinicians to facilitate their proper interpretation of test values in patients, it is apparent that much of the carefully derived scientific information is ignored in actual practice.     

On the frontline: pediatric obesity in the emergency department

Obesity among children is rising at an alarming rate. This study examines pediatric emergency department visits for children aged 2 to 17 years to determine the prevalence of normal, overweight, and obesity as well as to characterize discharge diagnosis and level of service among the different groups. The electronic emergency department medical record and billing service data were used in the review process. Body mass index (BMI) and percentiles were calculated using the Centers for Disease Control formulas with overweight being defined as BMI between 85th and 94th sex- and age-specific percentiles and obesity as greater than 95th sex- and age-specific percentile. The study was reviewed and approved by the institutional review board. Of the 596 patients meeting inclusion criteria, there was a predominance of African American and Hispanic patients. Approximately 53% (313) of patients were classified as normal weight, while 46% (272) of patients were either overweight or obese. The percentages of overweight and obesity were similar across racial/ethnic classifications, with a slight predominance of obesity among minority groups (30% and 35%, respectively, in minority groups vs 28% and 25%, respectively, in nonminority groups). There were no statistically significant differences between discharge diagnosis and level of service among the different weight categories. Rates of overweight and obesity in this predominately minority pediatric population were significantly greater than the published national rates. The impact of the epidemic of childhood obesity mandates the need for innovative strategies of weight control and reduction. Emergency departments routinely treat high-risk pediatric populations and can therefore serve as a resource for screening and early referral that has been previously untapped in combating childhood obesity.     

Coagulation/fibrinolysis disorders in the elderly

To establish reference intervals for the interpretation of hemostatic tests in the elderly, 11 hemostatic tests were performed on 120 elderly individuals(26 males and 94 females) aged 78.6 years in average. The subjects lived in hostel for the elderly, walked without assistance, and were independent in activities in daily living. In 25.8% to 93.3% of the subjects, the results of the tests, except for prothrombin time and thrombin-antithrombin III complex, deviated from reference intervals obtained from young healthy subjects. This suggests the necessity of setting up reference intervals for the elderly. Fibrinolysis was more activated than coagulation, although coagulation had been considered to be more activated because thrombosis is common in the elderly. Wilcoxon test on the test values of the early elderly(65 to 74 years of age) and late elderly(75 to 92 years of age) as well as the correlation coefficient for age and test values revealed that separate reference intervals for antithrombin III, protein C, D-dimer, and thrombomodulin should be established for the early elderly(65 to 74 years) and late elderly(75 years or over). Our proposed reference intervals for the elderly are appropriate for the diagnosis of disseminated intravascular coagulation.     

Criterion methods of body composition analysis for children and adolescents

The lack of chemical maturity, subsequent to normal growth and maturation, complicates the assessment of body composition in children. Even though known to overpredict percent body fat (%BF), the use of adult prediction equations is widespread in the pediatric literature. Many sex- and age-specific modified equations have been proposed. This study reports a cross-validation analysis of selected laboratory-based criterion methods in an attempt to identify the most appropriate reference which could be used in future validation studies of the more practical field/clinical testing methods. Subjects were 48 (24 boys and 24 girls) peripubertal children evenly distributed according to stage of maturation. Criterion measurements included body density (Db) by hydrostatic weighing, total body water (TBW) by deuterium oxide dilution, and total body mineral content (TMC) by dual energy x-ray absorptiometry. Five different prediction models were evaluated. Test-retest reliabilty was high (ICC = .970 to .999). Of the prediction models tested, the four-component model was considered the most accurate laboratory-based criterion model since it involves measurement of the primary constituents of fat-free mass. Based on high r² (≥.942) values, low standard errors of estimate (SEE = 1.8 %BF males, 1.1 %BF females); and low total prediction errors (TE = 1.9 %BF males, 2.0 %BF females), the Lohman age-adjusted prediction equation showed the best agreement with the four component model. If multiple testing facilities are unavailable, the Lohman two-component (Db) model would be the criterion method of choice. © 1993 Wiley-Liss, Inc.     

Quantitative measurement of FMRP in blood platelets as a new screening test for fragile X syndrome

Lessard M, Chouiali A, Drouin R, Sébire G, Corbin F. Quantitative measurement of FMRP in blood platelets as a new screening test for fragile X syndrome. The fragile X syndrome usually results from CGG repeats expansion and methylation of the FMR1 gene leading to the absence of expression of its encoded protein, fragile X mental retardation protein (FMRP). Therefore, its diagnosis is traditionally based on the detection of these molecular alterations. As an alternative, FMRP-based screening methods have been proposed over the years. Most of them are based on immunohistochemistry analyses applied to a restricted number of lymphocytes (100) or hair roots (10-20) with limited diagnosis potential. In this study, we describe a truly quantitative approach using a new model, the blood platelet, which can be recovered easily with very high purity (99.9%). FMRP levels in platelets were first measured in a control population (n = 124) and reference values were established. FMRP measurements were also performed in confirmed fragile X subjects. Receiver operating characteristic curve analysis has shown that our test can easily discriminate fragile X males and females from controls (area under curve, AUC = 0.948). Cognitive functions were also assessed in these individuals using age-specific Wechsler Intelligence Scales for Children and the Vineland Adaptive Behavior Scales. A proportional relationship between FMRP levels, intelligence quotient and adaptive behavior was observed among fragile X individuals, suggesting that our test would be able to detect fragile X cases and may predict cognitive functions.     

Clinical laboratory data and reference intervals standardized in Fukuoka

In Fukuoka whose population is approximately five million inhabitants, surveys on the accuracy of laboratory data have been performed by the Fukuoka Prefecture Medical Association for the last 30 years. We have been attempting to evaluate the data for routine use since 1988, and it has become possible to share laboratory data between all institutions in Fukuoka prefectures. As a result, reference intervals for 23 clinical chemistry analytes were established in 1995, to which were added in 1996 five serum protein constituents that have been utilized for clinical examinations. Methods for documentations and monitorings the data obtained in the prefecture were also established, standardization of the above analytes extended to 97% of the institutions in the prefecture. Results for 14 of the 23 clinical chemistry analytes have become highly reliable and clinically useful as differences between institutions in terms of results have narrowed. Standardization of other analytes is now in progress.     

Critical differences of clinical chemical components in blood from Red Danish dairy cows based on weekly measurements.

The critical difference, which may help to judge whether the difference between two consecutive analytical results may be safely ascribed to natural variation or not, was calculated for 12 clinical chemical components determined in blood samples collected once a week for 5 consecutive weeks from 19 clinically healthy Red Danish dairy cows. For each clinical chemical component, the total variance of the analytical results was divided into the component of variance between cows (S2Inter), the component of variance for weeks within cows (S2Intra) and the component of variance for measurements (S2Anal) using nested analysis of variance. The critical difference calculated in absolute values from S2Intra and S2Anal was 0.15 mu kat per 1 for alanine aminotransferase, 0.55 mu kat per 1 for aspartate aminotransferase, 0.57 mu kat per 1 for alkaline phosphatase, 0.14 mu kat per 1 for gamma-glutamyltransferase, 1.95 mu kat per 1 for creatine kinase, 2.23 mmol per 1 for urea, 22 mu mol per 1 for creatinine, 2.4 g per 1 for albumin, 10.0 g per 1 for serum protein Total, 0.71 mmol per 1 for glucose, 0.54 mmol per 1 for calcium and 0.25 mmol per 1 for magnesium. These critical differences may be used as guidelines to evaluate the difference between two consecutive analytical results in cows. However, the analytical results should not be assessed by the critical differences alone, but should also be compared with the corresponding reference intervals.     

Wolbachia infection and expression of cytoplasmic incompatibility in Armigeres subalbatus (Diptera: Culicidae)

Polymerase chain reaction screening revealed that Armigeres subalbatus (Coquillett), a vector of filariasis, was infected with the intracellular bacteria Wolbachia. Laboratory crosses between infected males and uninfected females resulted in less than half the number of offspring than control crosses between uninfected individuals when young (2- to 3-d-old) males were used in the cross. However, imcompatibility was lost when old (14- to 17-d-old) males were used. Field-collected females did not show detectable cytoplasmic incompatibility, and this may be because of the age at which males mate in the field. We used head pigment fluorescence levels to age field males collected from mating swarms, and found that 25-63% of swarming males were older than 13 d. Male age may be one factor influencing the observed low levels of cytoplasmic incompatibility detected in the field.