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BACKGROUNDCystic fibrosis (CF) is a complex autosomal recessive disease that continues to present unique diagnostic challenges. Because CF was first described in 1938, there has been a substantial growth of genetic and phenotypic information about the disorder. During the past few years, as more evidence has become available, a consortium of international experts determined that the 2008 guidelines from the CF Foundation needed to be reviewed and updated.CONTENTThe goal of this review is to highlight the latest advances in CF multidisciplinary care, together with the recent updates to the 2017 CF Foundation diagnostic guidelines.SUMMARYData from newborn screening programs, patient registries, clinical databases, and functional research have led to a better understanding of the CF transmembrane conductance regulator (CFTR) gene. Recent consensus guidelines have provided recommendations for clinicians and laboratorians to better assist with interpretation of disease status and related CF mutations. The highly recommended Clinical and Functional Translation of CFTR project should be the first resource in the evaluation of disease severity for CF mutations. Screen-positive newborns and patients with high clinical suspicion for CF are always recommended to undergo confirmatory sweat chloride testing with interpretations based on updated reference intervals. Every patient diagnosed with CF should receive genotyping, as novel molecular therapies are becoming standard of practice. The future of CF management must consider healthcare system disparities as CF transitions from a historically childhood disease to a predominantly adult epidemic.

Context.—Discrepant results for serum constituents were observed among peer groups in the College of American Pathologists Comprehensive Chemistry Survey.Objectives.—To assess the performance of serum albumin and total protein measurement procedures and to evaluate the commutability of the conventional survey specimens.Design.—A fresh frozen, off-the-clot serum sample was included along with 4 conventional survey specimens. The fresh frozen, off-the-clot serum sample was prepared in a manner expected to confer commutability with native clinical samples.Results.—For the fresh frozen, off-the-clot serum sample, the mean values for 17 peer-groups were −0.07 to 0.32 g/dL from the bromocresol green albumin designated comparison method, whereas 4 VITROS (Ortho Clinical Diagnostics, Rochester, New York) peer groups differed by −0.29 to −0.37 g/dL (15 of 21 differences [71%] had P < .001). For bromocresol purple albumin methods, the mean differences from the designated comparison method from 8 peer groups were 0.25 to 0.47 g/dL (all had P < .001). For total protein methods, 23 peer group mean values were −0.07 to 0.15 g/dL from the reference measurement procedure (12 of 24 [50%] had P < .001). The Beckman (Fullerton, California) Synchron LX20 had a bias of −0.30 g/dL (P Conclusions.—One (2.2%) of the instrument systems (Synchron) using bromocresol green and none (0%) of the instrument systems using bromocresol purple had satisfactory total-error performance for albumin measurement. Differences in results between bromocresol green and bromocresol purple methods precluded using common reference intervals for interpreting results for serum albumin. Eight of 9 instrument systems (86.5%) had satisfactory total-error performance for total protein measurement.

BACKGROUND Reference intervals from children are limited by access to healthy children and their limited blood volumes. In this study we set out to fill gaps in pediatric reference intervals for amino acids and steroid hormones using dried blood spots (DBS) from a cohort of the National Children's Study. METHODS Deidentified DBS annotated with age, birthweight, sex, and geographic location were obtained from 310 newborns aged 0–4 days and analyzed for 25 amino acids and 4 steroid hormones using LC-MS/MS. Nonparametric statistical approaches were used to generate the 2.5th–97.5th percentile distributions for newborns. Paired plasma/DBS specimens were used to mathematically transform DBS reference intervals to corresponding plasma intervals. RESULTS 10 of 25 DBS amino acid distributions were dependent on sex. There was little correlation with age, birthweight, or geographic location over the first 4 days of life. In most cases, transformation of DBS distributions to plasma distributions faithfully reflected independent studies of newborn plasma amino acid distributions. In general newborn steroid distributions were negatively correlated with age and birthweight over the first 4 days of life. Data distributions for the 4 steroids were not found related to geographic location, but testosterone concentrations displayed sex dependence. Transformation of DBS distributions to plasma intervals did not faithfully replicate other neonate steroid reference intervals determined directly with plasma. CONCLUSIONS These data demonstrate the feasibility and utility of deriving newborn reference intervals from large numbers of archived DBS samples such as those obtained from the National Children's Study biobank.

In 2003, the Chemistry Resource Committee of the College of American Pathologists introduced a new specimen in the Neonatal Bilirubin Survey. The specimen, consisting of human serum enriched with unconjugated bilirubin and thus resembling a clinical specimen, brought about an improvement in the accuracy of the measurement of bilirubin by laboratories participating in the Neonatal Bilirubin Survey. There was also an improvement in the specificity of methods measuring direct bilirubin. However, persisting inaccuracies and variability in laboratory performance have been traced to calibrators consisting of bovine serum spiked with unconjugated bilirubin and ditaurobilirubin; bovine serum causes underestimation of both bilirubins by 8 major chemical analyzers. To eradicate inaccuracy calibrators and Survey specimens should be made in human instead of bovine serum.

To determine the relationship between BiliChek TcB (Respironics, Marietta GA) and Doumas reference serum or plasma total bilirubin (TSB).Pooled samples with values assigned by the Doumas reference method were used to establish the relationship between a local laboratory and reference Doumas TSB. We then established the relationship between TcB and TSB in the 3 months before and after reassignment of calibrator setpoints undertaken to match the local laboratory to Doumas reference bilirubin values.Before calibrator setpoint reassignment TSB as measured in our laboratory overestimated Doumas reference bilirubin. After calibrator adjustment laboratory TSB was within 1.7-6.8 micromol/L (0.1-0.4 mg/dL) of Doumas reference values. Mean bias between BiliChek TcB and TSB was 42.8+/-22.2 micromol/L (2.5+/-1.3mg/dL) (n=94) before and 49.6+/-22.2 micromol/L (2.9+/-1.3mg/dL) (n=115) after calibration adjustment.BiliChek TcB significantly overestimates TSB as measured by the Doumas reference method.

Background Lactate is commonly used in septic patients and is a viable biomarker for trauma patients. Its pre-hospital use could assist triaging and managing patients with these conditions. Methods We evaluated the analytical performance of the point-of-care (POC) StatStrip Xpress Lactate Meter (Nova Biomedical) and compared it to the ABL 800 (Radiometer). We measured lactate in 250 adult and 250 pediatric whole blood samples in 2 laboratories. The performance of the POC meter was assessed by traditional linear regression and Bland-Altman plots, and locally-smoothed (LS) median absolute difference and maximum absolute difference (MAD and MaxAD) curves. Results The StatStrip was linear with acceptable reproducibility at clinically relevant concentrations. Correlation with the ABL800 showed a negative bias for both populations with slope, bias ± SD (% bias) of 0.78, − 0.4 ± 0.7 (− 14.5%) in children and 0.80–0.3 ± 0.6 (− 13.3%) in adults. The proportional bias appeared more significant at concentrations > 4 mmol/l (36.0 mg/dl). The StatStrip misclassified 7.6 and 8.8% pediatric and adult samples, respectively, to lower risk categories defined using guidelines driven cut-offs. The LS MAD curves identified one breakout, concentration where the LS MAD exceeds the total allowable error limit of 0.3 mmol/l (2.7 mg/dl), at lactate concentrations of 3.8 and 3.2 mmol/l (34.2 and 28.8 mg/dl) in the pediatric and adult curves, respectively. Breakthroughs, points at which the LS MaxAD curve exceeds the 95th percentile of MaxADs, occur at concentrations above 7.5 mmol/l (67.6 mg/dl) for both populations where the performance of the POC meter became erratic. We concluded that if serial lactate measurements are performed, the same method should be used for baseline and follow up measurements. The LS MAD and LS MaxAD curves allowed visual and quantitative mapping of the performance of the lactate POC meter over the range of concentrations measured. Conclusions This approach seems useful for the identification of points at which the performance of a POC meter differs significantly from a comparison method and thresholds of poor analytical performance.

Background: The analytic performance and accuracy of drug detection below Substance Abuse and Mental Health Services Administration (SAMHSA) cutoffs is not well known. In some patient populations, clinically significant concentrations of abused drugs in urine may not be detected when current SAMHSA cutoffs are used. Our objectives were to define the precision profiles of three immunoassay systems for drugs of abuse and to evaluate the accuracy of testing at concentrations at which the CV was Methods: Drug-free urine was supplemented with analytes to assess the precision in three commercial drugs-of-abuse immunoassay systems below the SAMHSA-dictated cutoffs for amphetamines, opiates, benzoylecgonine, phencyclidine, and cannabinoids. Consecutive urine samples with signals associated with a CV Results: The CV of all immunoassay systems tested remained Conclusion: The precision of three commercial immunoassay systems for drugs-of-abuse screening is adequate to detect drugs below SAMHSA cutoffs. Knowledge of the positive predictive values of screening immunoassays at lower cutoff concentrations could enable efficient use of confirmatory testing resources and improved detection of illicit drug use.

Background: Almost all newborns in the US are screened at birth for multiple inborn errors of metabolism using tandem mass spectrometry. Screening tests are designed to be sufficiently sensitive so that cases are not missed. The NACB recognized a need for standard guidelines for laboratory confirmation of a positive newborn screen such that all babies would benefit from equal and optimal follow-up by confirmatory testing.Methods: A committee was formed to review available data pertaining to confirmatory testing. The committee evaluated previously published guidelines, published methodological and clinical studies, clinical case reports, and expert opinion to support optimal confirmatory testing. Grading was based on guidelines adopted from criteria derived from the US Preventive Services Task Force and on the strength of recommendations and the quality of the evidence. Three primary methods of analyte measurement were evaluated for confirmatory testing including measurement of amino acids, organic acids, and carnitine esters. The committee graded the evidence for diagnostic utility of each test for the screened conditions.Results: Ample data and experience were available to make strong recommendations for the practice of analyzing amino acids, organic acids, and acylcarnitines. Likewise, strong recommendations were made for the follow-up test menu for many disorders, particularly those with highest prevalence. Fewer data exist to determine the impact of newborn screening on patient outcomes in all but a few disorders. The guidelines also provide an assessment of developing technology that will fuel a refinement of current practice and ultimate expansion of the diseases detectable by tandem mass spectrometry.Conclusions: Guidelines are provided for optimal follow-up testing for positive newborn screens using tandem mass spectrometry. The committee regards these tests as reliable and currently optimal for follow-up testing. .

To the Editor: We commend Don-Wauchope et al., who assessed 11 National Academy of Clinical Biochemistry (NACB)1 laboratory medicine practice guidelines (LMPGs) with the AGREE II (Appraisal of Guidelines for Research and Evaluation II) instrument (1), and we thank Bossuyt for his accompanying editorial (2). The results of this study are helpful but are not unexpected. These LMPGs were developed over several years. The 8 nonarchived LMPGs published in the past 5 years used 4 different systems for grading and weighting practice recommendations. One system that several LMPG committees have used is a modified US Preventive Services Task Force (USPSTF) system. A second system used for 2 LMPGs was that of the American College of Cardiology and the American Heart Association. At times, NACB LMPG committees have used clinical societies' systems when these groups are primary collaborators in LMPG development, as well as significant end users of the LMPG. A third system created by the authors of 3 LMPGs focused on tumor marker tests. This unique system was developed by LMPG members who felt that considerable heterogeneity in clinical oncology practice guidelines failed to indicate a preference in any clinical society's system. Finally, authors of the most recent diabetes …

Background: The diagnosis and management of hyperbilirubinemia in the newborn requires accurate and precise bilirubin determinations. We evaluated the current status of bilirubin measurements in US laboratories by examining data submitted by laboratories participating in the College of American Pathologists (CAP) Neonatal Bilirubin (NB) and Chemistry (C) Surveys. Methods: We analyzed specimens from the CAP NB and C Surveys by the reference method for total bilirubin in three laboratories. The reference method bilirubin values were compared with bilirubin values reported by Survey participants. Results: The imprecision (CV) for all instruments combined (CAP-All Instruments) ranged from 4.7% to 5.6% at the bilirubin concentrations tested. The CVs of the four most commonly used instruments were smaller, ranging from 1.9% to 4.5%. Differences between bilirubin values by the reference method and mean values from the four most common instruments ranged from −21.6% to 10.9%. When the same specimens from the NB Surveys were used in the C Surveys, the Vitros values were strikingly different from those of the NB Surveys. The use of different methods in the NB and C Surveys coupled with the presence of a nonhuman protein base and ditaurobilirubin (DTB) in the Survey specimens accounted for the discrepant results. Conclusions: The evaluation of accuracy is impossible from the CAP Surveys because the specimens consist of bovine serum containing a mixture of unconjugated bilirubin and DTB. For the evaluation of accuracy, we recommend that Survey specimens consist of human serum enriched with unconjugated bilirubin.

We describe a case of extreme hypercholesterolemia, mediated by lipoprotein X, in a 12-year-old Caucasian female who underwent an unrelated allogenic bone marrow transplant for relapsed acute myelocytic leukemia (AML). Her post-transplant course was complicated by severe chronic graft-versus-host disease (GVHD) of the liver. Previously normal serum cholesterol and triglycerides rose to 1,122 mg/dl (29.0 mmol/L) and 1,100 mg/dl (12.4 mmol/L), respectively. Serum cholesterol appeared to be dominantly carried by lipoprotein X. Intra-hepatic cholestasis leading to reflux of bile lipoproteins into the blood stream and subsequent formation of lipoprotein X appears to be the mechanism underlying this phenomenon.