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Background: 1,25-dihydroxyvitamin D (1,25(OH)2D), the biologically active vitamin D metabolite, plays a critical role in calcium and phosphate homeostasis. 1,25(OH)2D is measured to assess calcium and phosphate metabolism, particularly during periods of profound growth and development. Despite its importance, no reliable pediatric reference interval exists, with those available developed using adult populations or out-dated methodologies. Using the fully automated chemiluminescence immunoassay by DiaSorin, we established 1,25(OH)2D pediatric reference intervals using healthy children and adolescents from the CALIPER cohort. Methods: Serum samples from healthy subjects (0 to 2D using the DiaSorin LIAISON XL assay and age-specific reference intervals were established. The Mann-Whitney U-test was used to determine seasonal differences. Pooled neonatal and infantile samples were quantified using liquid chromatography tandem mass spectrometry (LC-MS/MS) to determine if elevated concentrations during the first year of life may be attributed to cross-reacting moieties. Results: Three reference interval age partitions were required with highest levels in subjects 0 to 2D concentration was not significantly affected by seasonal variation or sex. Elevated 1,25(OH)2D concentrations in neonatal and infantile samples may be the result of an interfering substance. The absence of 3-epi-1,25-dihydroxyvitamin D in the pooled samples makes it unlikely to be the interfering moiety. Conclusions: Pediatric reference intervals for 1,25(OH)2D were established to improve test result interpretation in children and adolescents. 1,25(OH)2D is elevated in a proportion of neonates and infants, which may be the result of a cross-reacting moiety.

Objective To evaluate the disease burden of placental maternal vascular malperfusion pathology in a low-risk nulliparous population and test the hypothesis that a multiparameter model in the second trimester can predict maternal vascular malperfusion with high precision. Methods A single-center, prospective cohort study was conducted in healthy nulliparous women. Maternal vascular malperfusion disease burden was estimated by incidence, relative risk (RR), and population-attributable risk percent. Maternal risk factors, serum biomarkers, Doppler, and placental morphologic ultrasonography were examined in isolation and in combination for prediction of this placental pathology. Results The incidence of maternal vascular malperfusion pathology was 8.4% (72/856). Women with pathology had higher risk of preeclampsia (8.33% compared with 1.79%; RR 4.67, 95% CI 1.85-11.77%; population-attributable risk 23.6%, 95% CI 16.9-31.6%), small for gestational age (SGA) (47.22% compared with 9.45%; RR 5.00, 95% CI 3.6-6.93%; population-attributable risk 25.2%, 95% CI 22.1-28.5%), and the composite of adverse outcomes (defined as SGA or preeclampsia) (47.22% compared with 10.59%; RR 4.46, 95% CI 3.25-6.13; population-attributable risk 22.5%, 95% CI 19.8-25.5%). The combination of parameters was superior to individual modalities alone in predicting maternal vascular malperfusion, but achieved only moderate precision (area under the curve 0.77, 95% CI 0.71-0.84). Conclusion One in 12 healthy nulliparous women develop maternal vascular malperfusion placental pathology, and these pregnancies had a 4.5 times higher risk of developing preeclampsia or delivering a SGA neonate compared with those without this pathology. A multiparameter model achieved modest precision to predict placental maternal vascular malperfusion. Importantly, in low-risk pregnancies, maternal vascular malperfusion accounts for one fourth of pregnancy outcomes with SGA or preeclampsia. The low population-attributable risk of this placental pathology for SGA and preeclampsia illustrates the importance of discovering novel associations to reduce the disease burden of these pregnancy complications.

It is timely with interest in prostate cancer screening rekindled by the recently revised and updated recommendations issued by the United States Preventative Services Task Force (USPSTF)3 (1) that this cancer-themed issue of the Journal of Applied Laboratory Medicine includes the study by Higgins and coauthors (2), who evaluated the analytical performance of one such screening test designed to avoid the overdiagnosis of indolent prostate cancer, the 4Kscore. Such information is also timely, if not overdue, given that this test has been in use since 2014 with only a single published Abstract (3), presented at the 2015 AACC Annual Meeting, describing the test's analytical performance and …

Background The diagnostic utility of laboratory tests in paediatric medicine relies heavily on the availability of appropriate reference intervals (RIs). The Canadian Laboratory Initiative on Paediatric Reference Intervals (CALIPER) has established a comprehensive database of covariate-stratified RIs for many paediatric laboratory tests using a large, healthy reference population. Several automated analysers in widespread use in clinical laboratories have already been studied. Here, we extend the testing to Roche immunoassays and report, for the first time, comprehensive paediatric RIs for 17 endocrine and special chemistry markers. Methods A total of 741 healthy children and adolescents (1 day to Results Reference values for all analytes measured required age partitioning, particularly during early life and throughout adolescence. Of the 17 analytes measured, eight required sex partitioning, including ferritin, thyroid stimulating hormone (TSH), total triiodothyronine (TT3) and all fertility/sex hormones, except prolactin. Conclusions This is the first study to determine accurate paediatric RIs for Roche immunoassays. RIs were generally similar to those previously published by CALIPER on other analytical platforms, highlighting the reproducibility of age- and sex-specific trends in reference values observed across the paediatric age range. The RIs established in this study will improve the accuracy of test result interpretation and clinical decision-making in clinical laboratories utilising Roche immunoassays.

To the Editor: International societies and expert groups recommend using sex-specific upper reference limits (URLs)1 for interpretation of high-sensitivity cardiac troponin (hs-cTnI/T) assays (1, 2). Despite advances in our understanding of cTn in adults, the effect of age and sex on cTn in pediatric populations is less understood. The Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) previously determined 97.5th and 99th percentiles for the Abbott hs-cTnI assay in a healthy pediatric cohort (3). These data represented the first attempt to characterize hs-cTnI in healthy children but did not include neonates nor were sex-specific differences evident. It is unclear, however, what cTnT URLs would be in this population because cTnT is a different protein and there are differences in analytical sensitivity and specificity between hs-cTnT and hs-cTnI assays (1–4). Establishing pediatric reference values for cTn is important because its measurement has several clinical indications in pediatrics, including monitoring children with postoperative myocarditis and congenital pediatric heart disease. Serum samples from 598 children and adolescents were selected from the CALIPER biobank. Samples from participants

SUMMARY Objective This study aimed to assess the quantitative impact of maternal weight discrepancy on the screen result for Down syndrome when using Integrated Prenatal Screening and First Trimester Combined Screening. Methods The study population consisted of 78 165 women undergoing prenatal screening in Ontario, Canada, and 158 pregnancies affected with Down syndrome at one Ontario center. The study assessed quantitative alterations of the multiple of the median values of first and second-trimester serum markers and the risks of Down syndrome at a set of theoretical weight discrepancies. Results Weight discrepancies have the greatest impact on screening results when the initial risk is close to the risk cut-off. When the weight discrepancy is 5 lb or greater and the denominator of the initial risk is within 50 of the risk cut-off, the chance that a screen result will change from positive to negative or from negative to positive is 47–55% for women undertaking Integrated Prenatal Screening. This chance is 33–43% for women undertaking First Trimester Combined Screening. Conclusion A weight discrepancy of five or more pounds has a significant impact on the risk of Down syndrome; correction of maternal weight would improve the accuracy of the screening test. © 2013 John Wiley & Sons, Ltd.

Background: Updated National Academy of Clinical Biochemistry (NACB) Laboratory Medicine Practice Guidelines for the use of tumor markers in the clinic have been developed.Methods: Published reports relevant to use of tumor markers for 5 cancer sites—testicular, prostate, colorectal, breast, and ovarian—were critically reviewed.Results: For testicular cancer, α-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase are recommended for diagnosis/case finding, staging, prognosis determination, recurrence detection, and therapy monitoring. α-Fetoprotein is also recommended for differential diagnosis of nonseminomatous and seminomatous germ cell tumors. Prostate-specific antigen (PSA) is not recommended for prostate cancer screening, but may be used for detecting disease recurrence and monitoring therapy. Free PSA measurement data are useful for distinguishing malignant from benign prostatic disease when total PSA is Conclusions: Implementation of these recommendations should encourage optimal use of tumor markers.

Background: This report presents updated National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines summarizing quality requirements for the use of tumor markers. Methods: One subcommittee developed guidelines for analytical quality relevant to serum and tissue-based tumor markers in current clinical practice. Two other subcommittees formulated recommendations particularly relevant to the developing technologies of microarrays and mass spectrometry. Results: Prerequisites for optimal use of tumor markers in routine practice include formulation of the correct clinical questions to ensure selection of the appropriate test, adherence to good clinical and laboratory practices (e.g., minimization of the risk of incorrect patient and/or specimen identification, tube type, or timing), use of internationally standardized and well-characterized methods, careful adherence to manufacturer instructions, and proactive and timely reactions to information derived from both internal QC and proficiency-testing specimens. Highly desirable procedures include those designed to minimize the risk of the reporting of erroneous results attributable to interferences such as heterophilic antibodies or hook effects, to facilitate the provision of informative clinical reports (e.g., cumulative and/or graphical reports, appropriately derived reference intervals, and interpretative comments), and when possible to integrate these reports with other patient information through electronic health records. Also mandatory is extensive validation encompassing all stages of analysis before introduction of new technologies such as microarrays and mass spectrometry. Provision of high-quality tumor marker services is facilitated by dialogue involving researchers, diagnostic companies, clinical and laboratory users, and regulatory agencies. Conclusions: Implementation of these recommendations, adapted to local practice, should encourage optimization of the clinical use of tumor markers.

Type 2 diabetes mellitus (DM) is associated with increased cardiovascular risk, in part due to accelerated subclinical atherosclerosis. Electrocardiographic (ECG) and ankle–brachial index (ABI) abnormalities are used to screen for cardiovascular risk in the clinic. However, their capacity to identify patients with type 2 DM with nonobstructive subclinical atherosclerosis is unknown. Associations of ECG and ABI abnormalities with coronary artery calcium (CAC), a measure of coronary atherosclerosis, were examined using multivariable ordinal regression modeling in 589 asymptomatic patients with type 2 DM. Sensitivity, specificity, and positive and negative predictive values were determined. CAC was prevalent (44% CAC >100; 32% CAC >75th percentile score) despite normal electrocardiograms (64%) and ABIs (97%) in most subjects. Neither ECG nor ABI changes predicted CAC after adjusting for age, gender, and race. ECG abnormalities were neither sensitive nor specific for detection of CAC >100, >400, or >75th percentile (sensitivities 0.43, 0.45, and 0.34; specificities 0.69, 0.66, and 0.63, respectively). ABI abnormalities were not sensitive (0.03, 0.04, and 0.03) but had high specificity (0.98, 0.98, and 0.98). In subjects with normal electrocardiograms and ABIs, extensive CAC was remarkably prevalent (CAC >100 in 24%). In conclusion, ECG and ABI abnormalities failed to detect patients with subclinical coronary atherosclerosis and therefore may be of limited value in identifying many asymptomatic patients with type 2 DM at increased risk of cardiovascular disease.

We report the measure of prostate-specific antigen (PSA) from extracts of blood dried on filter paper. Five 3-mm (diameter) paper discs containing approximately 25 microL of dried whole blood were punched from the filter paper and extracted with 500 microL of buffer. Recovery of PSA was > 92%. Imprecision of the filter paper procedure was 0.35 micrograms/L. PSA recovery was unaffected whether blood was applied to the filter as one 85-microL aliquots, two 43-microL aliquots, or three 28-microL aliquots. PSA is contained in the plasma fraction. Variation in hematocrit from 0.61 to 0.31 caused 1 month at -20 to 37 degrees C and showed no loss of recovery after being mailed to a hot climate. We conclude that the filter paper procedure can reliably distinguish normal from increased concentrations of PSA and that it could facilitate screening to detect occult prostate cancer in large-scale mail-in programs to centralized laboratories.

Objective To investigate the associations between four defined adverse pregnancy outcomes and levels of first and second trimester maternal serum markers focusing in particular on how well combinations of markers predict these adverse outcomes. Methods This was a retrospective review of associations between first and second trimester serum markers and adverse pregnancy outcomes among 141 698 women who underwent prenatal screening for Down syndrome in Ontario, Canada. Detection rates (DR), false positive rates (FPR), and odds ratios were estimated using both single and combinations of markers for the adverse outcomes defined. Results Women with decreased second trimester unconjugated oestriol (uE3), deceased first trimester maternal serum pregnancy-associated plasma protein A (PAPP-A), increased second trimester serum alpha fetoprotein (AFP), or increased second trimester total human chorionic gonadotrophin (hCG) were at greater risk of developing adverse pregnancy outcomes. At a 5% FPR, combinations of these markers predicted at best 33.3% of fetal loss and 31.5% of preterm births (PTB) before 32 weeks of gestation. Conclusion There are significant associations between the levels of first and second trimester serum markers and adverse obstetric outcomes. However, even combinations of these markers can only predict adverse obstetric outcomes with modest accuracy. Copyright © 2010 John Wiley & Sons, Ltd.

Objectives To evaluate the performance of integrated prenatal screening (IPS) and first trimester combined screening (FTS) for trisomy 21 in a large Canadian urban center. Method Prospective data collection on women having FTS at one center from 1 November 2003 to 31 December 2005, or IPS at another from 1 January 2003 to 31 December 2005. A positive screen was defined as adjusted risk for trisomy 21 ≥ 1/200 at term or nuchal translucency ≥ 3.5 mm. Results 32 227 and 14 487 women were screened in the IPS and FTS programs, respectively. Detection rates (DRs) and positive rates (PRs) for trisomy 21 were 88.4% (95% CI: 81.6–91.5) and 3.3% (95% CI: 3.1–3.5) for IPS, and 83.9% (95% CI: 74.7–93.0) and 4.0% (95% CI: 3.7–4.3) for FTS. DR adjusted for viability bias was 85.2% for IPS and 78.6% for FTS. Applying both the screens to the 78 134 women who submitted prenatal screens in Ontario in 2005, thereby eliminating the effect of differences in the distribution of maternal age between screens, gave a DR (corrected for viability bias) and PR of 81 and 3.1% for IPS, and 76 and 3.4% for FTS. Conclusions Both IPS and FTS perform well and are feasible in a practical clinical setting. Copyright © 2008 John Wiley & Sons, Ltd.

The National Academy of Clinical Biochemistry (NACB) Laboratory Medicine Practice Guidelines for Use of Tumor Markers are intended to encourage more appropriate use of tumor marker tests by primary care physicians, hospital physicians and surgeons, specialist oncologists, and other health professionals. This introduction accompanies the e-publication of 2 reports summarizing NACB Quality Requirements for use of tumor markers in clinical practice (1) and NACB Guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers (2). Two further reports will follow, summarizing the NACB Guidelines for use of tumor markers in liver, pancreatic, gastric, bladder, and cervical cancers and the NACB Guidelines for use of tumor markers in parathyroid, thyroid, neuroendocrine and lung cancers, monoclonal gammopathies, and melanoma. Here we report the updating and extension of practice guidelines first proposed in 2002 (3). Undertaken under the direction of a steering committee appointed by the NACB (Table 1⇓ ), this process involved consideration of 16 specific cancer sites, together with quality requirements for well-established tumor markers and tumor markers being developed by use of new technologies (Table 2⇓ ). With its wide scope, this project is one of the most comprehensive and complex of its type to date. The draft guidelines were posted on the NACB website in July 2005 and were presented as an EduTrak at the 2005 Joint AACC/IFCC Annual meeting in Orlando, Florida. Informed comment was also actively sought from individuals, organizations, and other interested parties. View this table: Table 1. Steering committee for NACB Laboratory Medicine Practice Guidelines on Use of Tumor Markers in clinical practice. View this table: Table 2. Subjects and subcommittee members for NACB Laboratory Medicine Practice Guidelines on Use of Tumor Markers in clinical practice. Nineteen subcommittees developed draft guidelines (Table 2⇑ ). Subcommittee members included individuals with extensive expertise in the science, technology, and clinical practice …

Objective To determine using a simplified study design trimester-specific FT4 reference intervals in pregnancy with the Roche Modular immunoassay in routine use. Design and methods Surplus blood from 300 women in each trimester, drawn at documented times in the gestation, and from 40 age-matched nonpregnant women were assayed for FT4, thyroid stimulating hormone (TSH) and antithyroid peroxidase autoantibody (anti-TPO). Results After excluding women positive for anti-TPO and with abnormal TSH, reference intervals were calculated as 12.5–19.1 pmol/L (nonpregnant group), 11–19 pmol/L (first trimester), 9.7–17.5 pmol/L (second trimester) and 8.1–15.3 pmol/L (third trimester). 3rd trimester FT4 was significantly lower than that of the second trimester (p

Melatonin may protect against breast cancer. Light and other factors influence melatonin, but the evidence is limited. The authors conducted a study to determine factors related to melatonin. Women volunteers recruited in Toronto, Canada, from 2002 to 2004 collected urine for three nights (winter and summer), took periodic light measurements, and recorded exposures in a diary. The relation of each variable to log-transformed creatininecorrected 6-sulfatoxymelatonin in overnight urine was determined by use of generalized estimating equation linear regression. The final model was based on 1,054 measurement days from 213 participating women. None of the light variables was related to the log of 6-sulfatoxymelatonin. A significant interaction between season and day length was included in the final model. The most significant factor was duration of exercise (b ¼ 0.072; p ¼ 0.004, two-tailed), which increased the amount of melatonin produced. Exercise duration later in the day was more significant (b ¼ 0.108; p ¼ 0.0009, two-tailed). There was no difference between moderate or strenuous exercise. The failure to find a relation between light brightness and melatonin may be due to the difficulty of measuring this, as well as the importance of the light spectrum, which could not be measured. It is possible that the protective effect of exercise with respect to breast cancer may operate in part through an effect on melatonin. breast neoplasms; exercise; light; melatonin; women