Unnecessary Follow-up Testing Research Articles

Cystic fibrosis newborn screening in Switzerland – evaluation and scenarios for improvement after 11 years of follow-up

BackgroundNewborn bloodspot screening (NBS) for cystic fibrosis (CF) is important for early diagnosis and treatment. However, screening can lead to false-positive results leading to unnecessary follow-up tests and distress. This study evaluated the 11-year performance of the Swiss CF-NBS programme, estimated optimal cut-offs for immunoreactive trypsinogen (IRT), and examined how simulated algorithms would change performance. MethodsThe Swiss CF-NBS is based on an IRT–DNA algorithm with a second IRT (IRT-2) as safety net. We analysed data from 2011 to 2021, covering 959,006 IRT-1 analyses and 282 children with CF. We studied performance based on European Cystic Fibrosis Society (ECFS) standards including sensitivity, specificity, positive predictive value (PPV), false negative rate, and second heel-prick tests; identified optimal IRT cut-offs using receiver operating characteristics (ROC) curves; and calculated performance for simulated algorithms with different cut-offs for IRT-1, IRT-2, and safety net. ResultsThe Swiss CF-NBS showed excellent sensitivity (96 %, 10 false negative cases) but moderate PPV (25 %). Optimal IRT-1 and IRT-2 cut-offs were identified at 2.7 (>99th percentile) and 5.9 (>99.8th percentile) z-scores, respectively. Analysis of simulated algorithms showed that removing the safety net from the current algorithm could increase PPV to 30 % and eliminate >200 second heel-prick tests per year, while keeping sensitivity at 95 %. ConclusionThe Swiss CF-NBS program performed well over 11 years but did not achieve the ECFS standards for PPV (≥30 %). Modifying or removing the safety net could improve PPV and reduce unnecessary follow-up tests while maintaining the ECFS standards for sensitivity.

A-335 Pediatric Cortisol Reference Intervals (RI): Impact of Age-Specific RI on the Rate of Abnormal “Low” Cortisol Results

Abstract Background Serum cortisol, measured by automated immunoassay, is a rapid test used for the initial assessment of adrenal dysfunction. Physiologic serum cortisol concentrations are influenced by many factors including diurnal variation, stress, and patient age. In the absence of established pediatric reference intervals (RIs), our laboratory has utilized adult RIs to flag pediatric cortisol results as abnormally high or low in the electronic health record. However, pediatric cortisol RIs recently defined by the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) are considerably lower than the adult RIs currently in use. This could cause pediatric cortisol results to be incorrectly flagged as “low” when they are within the age-specific RI and lead to unnecessary follow-up testing. The aim of this study was to determine the impact of implementing CALIPER pediatric cortisol RIs on the rate of “low” result flagging for pediatric patients. Methods AM cortisol results for patients age <18 years reported between 10/2012- 09/2022 were obtained from the Mayo Clinic data repository. These results contained values measured by both Beckman Access (n = 3 818) and Roche Cobas (n = 625) immunoassays. Results classified as abnormal “low” by current adult RIs (Beckman: 7–25 mcg/dL, Roche: 4.8–20 mcg/dL) were compared to results which would flag low according to the appropriate method- and age-specific RIs defined by CALIPER (Beckman: 1-<13 yrs 2.19–12.8 mcg/dL, 13-<16 yrs 3.03–17.1 mcg/dL, 16-<19 yrs 3.78–19.4 mcg/dL; Roche: <1 yr 0.58–17.2 mcg/dL, 1-<12 yrs 2.39–14.9 mcg/dL, 12-<19 yrs 3.63–17.4 mcg/dL). The proportion of results flagging low by adult versus pediatric RI were compared by chi-squared test, with P < 0.05 considered significant. Results For Beckman, the percentages of pediatric patient cortisol results flagging low using the adult RI versus (vs) the pediatric age-specific RI were: 35% vs 7% for 1–12 years of age (P < 0.001, n = 1866), 22% vs 5% for 13–15 years (P < 0.001, n = 966), and 16% vs 5% for 16–18 years (P < 0.001, n = 986). For Roche, the same analysis yielded: 52% vs 9% for 0–1 years (P = 0.001, n = 23), 14% vs 8% for 1–11 years (P = 0.03, n = 238), and 9% vs 6% for 12–18 years (P = 0.16, n = 364). Conclusion The implementation of pediatric RIs for serum cortisol will have a significant impact on the number of “low” result flags for patient results on both Beckman and Roche platforms. Statistically significant decreases in the percentage of low result flags were observed on both platforms for all age ranges except for the age bracket of 12–18 years by Roche. Furthermore, pediatric RIs appeared to produce more consistent rates of abnormal results across methods and age ranges, with all groups flagging low at a rate of 5–9%, whereas the same age ranges with adult RIs flagged at rates ranging from 9–52%. Lowering the RIs for pediatric cortisol to more appropriate ranges as identified by CALIPER will decrease the number of “low” flag results. This has the potential to decrease unnecessary follow-up, including repeat testing and further diagnostic procedures such as ACTH stimulation testing. Implementation of pediatric RIs has potential benefits regarding stress and cost for patients and parents, alarm fatigue for physicians, and utilization of laboratory resources.

Approach to the Patients with Elevated CA 19-9

With the widespread adoption of health check-ups, tumor markers are being used for screening healthy individuals without symptoms related to cancer. Although CA 19-9 is known to have diagnostic value when a patient presents with symptoms, the evidence for its clinical value as a cancer screening test in asymptomatic patients is still lacking. However, patients who experience an increase in CA 19-9 levels may feel anxious about the possibility of having cancer and may seek medical attention. If the CA 19-9 level is elevated, it may be necessary to consider initial testing for malignant tumors of the pancreas. It should be recognized that the level can also increase in malignant tumors of the gastrointestinal tract, thyroid, and reproductive organs. Since the CA 19-9 levels can also increase in various benign diseases, it is important to evaluate if there is an underlying benign disease through appropriate testing and follow-up to reduce patient anxiety and discontinue unnecessary follow-up tests.

Establishing 17-Hydroxyprogesterone Cutoff Values for Congenital Adrenal Hyperplasia in Preterm, Low Birth Weight, and Sick Newborns.

Newborn screening for congenital adrenal hyperplasia (CAH) has benefits with a high adoption rate worldwide. It also has problems of high false positives, which can cause stress to the patient's family with economic losses and unnecessary visits of newborns to hospitals. Therefore, we investigated the influence of birth weight (BW), gestational age (GA), and GA with sampling time on 17-hydroxyprogesterone (17-OHP) concentration and attempted to establish the 17-OHP cutoff values in preterm, low birth weight (LBW), and sick newborns. Newborns (n=1,071) born between October 2020 and January 2022 were screened for CAH. Samples from neonates were collected on filter paper with the heel prick method. 17-OHP concentration was measured by time-resolved immunofluorescence with an AutoDELFIA Neonatal 17-hydroxyprogesteron kit and grouped in relation to BW, GA, and GA with sampling time. The median age of newborns at neonatal sample collection was 6 days. 17-OHP concentration showed a statistically significant negative correlation with BW (r=-0.488, p<0.001) and GA (r=-0.560, p<0.001). Full-term and preterm subgroups had a similar decreasing tendency of 17-OHP concentration with increasing sampling time. Application of newly establishing cutoff criteria significantly reduced recall rates to 1.16%, 0.9%, and 1.75% according to each criterion of BW, GA, and GA with sampling time, respectively. This study presents new 17-OHP cutoff values for preterm, LBW, and sick newborns. These data in our laboratory can be used as a reference by other laboratories for establishing new cutoff criteria to help lower the high recall rate and reduce unnecessary follow-up tests.

Consumer health informatics approach for personalized cancer screening decisions using utility functions.

A consumer health informatics approach is used to investigate the development of a patient-centered decision support system (DSS) with individualized utility functions. It supports medical decisions that have uncertain benefits and potential harms. Its use for accepting or declining cancer screening is illustrated. The system's underlying optimization model incorporates two user-specific utility functions-one that quantifies life-saving benefits and one that quantifies harms, such as unnecessary follow-up tests, surgeries, or treatments. The system requires sound decision making. Therefore, the decision making process was studied using a decision aid in the form of a color-coded matrix with the potential outcomes randomly placed in proportion to their likelihoods. Data were collected from 48 study participants, based on a central composite experimental design. The results show that the DSS can be effective, but health consumers may not be rational decision makers.

Lung Nodule Detection via Deep Reinforcement Learning.

Lung cancer is the most common cause of cancer-related death globally. As a preventive measure, the United States Preventive Services Task Force (USPSTF) recommends annual screening of high risk individuals with low-dose computed tomography (CT). The resulting volume of CT scans from millions of people will pose a significant challenge for radiologists to interpret. To fill this gap, computer-aided detection (CAD) algorithms may prove to be the most promising solution. A crucial first step in the analysis of lung cancer screening results using CAD is the detection of pulmonary nodules, which may represent early-stage lung cancer. The objective of this work is to develop and validate a reinforcement learning model based on deep artificial neural networks for early detection of lung nodules in thoracic CT images. Inspired by the AlphaGo system, our deep learning algorithm takes a raw CT image as input and views it as a collection of states, and output a classification of whether a nodule is present or not. The dataset used to train our model is the LIDC/IDRI database hosted by the lung nodule analysis (LUNA) challenge. In total, there are 888 CT scans with annotations based on agreement from at least three out of four radiologists. As a result, there are 590 individuals having one or more nodules, and 298 having none. Our training results yielded an overall accuracy of 99.1% [sensitivity 99.2%, specificity 99.1%, positive predictive value (PPV) 99.1%, negative predictive value (NPV) 99.2%]. In our test, the results yielded an overall accuracy of 64.4% (sensitivity 58.9%, specificity 55.3%, PPV 54.2%, and NPV 60.0%). These early results show promise in solving the major issue of false positives in CT screening of lung nodules, and may help to save unnecessary follow-up tests and expenditures.

Transient Hepatitis B Surface Antigen Positivity Following Vaccination

Background Interpretation of hepatitis B virus (HBV) testing is notoriously challenging. An under-recognized pitfall is transient positivity of hepatitis B surface antigen (HBsAg) following immunization in healthy individuals. We present the case of a patient who was referred for a positive HBsAg following routine immunization. Case A 21-year-old female was referred for possible HBV infection following routine testing for sexually transmitted infections (STIs). The patient had a past medical history of iron deficiency anemia and irregular menses. She had unprotected intercourse with a single partner 5 months prior to evaluation, and denied medications, prior surgery, transfusion of blood products, or intravenous drug use. Her paternal grandfather had an unknown type of liver cancer, but neither of her parents had any known liver disease. Review of the patient's medical record revealed she underwent her second HBV vaccination the day before her primary physician ordered STI testing. A viral hepatitis panel was drawn 30 hours following her vaccination, and was qualitatively positive for HBsAg, which prompted extensive follow-up lab testing and Gastroenterology consultation. The patient's physical exam was without stigmata of chronic liver disease, and was otherwise unremarkable. Repeat testing drawn 6 days after vaccination demonstrated normal liver-associated enzymes, and negative hepatitis B surface antibody (HBsAb), HBsAg, anti-hepatitis B core IgG and IgM, hepatitis B e-antigen and antibody, and undetectable HBV DNA by PCR. Discussion Current HBV vaccines utilize purified HBsAg derived from recombinant yeast and may result in transient HBsAg positivity, which has been reported in a variety of patient populations. The reported incidence ranges from 13-32%, and the phenomenon is particularly common in end-stage renal disease and hemodialysis patients. HBsAg positivity has been reported as early as 6 hours following vaccination, typically peaks by 2-3 days, and nadirs by 14 days. Our patient's HBsAg positivity reverted within 6 days of vaccine exposure, but if testing is indicated or clinical uncertainty exists, we recommend deferring at least 2 weeks following vaccination. Conclusions Transient HBsAg positivity is common following vaccination, and usually does not extend beyond 14 days. Deferring HBV testing for an appropriate period may prevent not only patient anxiety, but also expensive and unnecessary follow-up testing and specialist consultation.

Measurement of anti-DFS70 antibodies in patients with ANA-associated autoimmune rheumatic diseases suspicion is cost-effective.

The presence of antinuclear antibodies (ANA) is associated with a wide range of ANA-associated autoimmune rheumatic diseases (AARD). The most commonly method used for the detection of ANA is indirect immunofluorescence (IIF) on HEp-2 cells. This method is very sensitive but unspecific. As a consequence, ANA testing on HEp-2 substrates outside a proper clinical specialist framework may lead to inappropriate referrals to tertiary care specialists and, worst case inappropriate and potentially toxic therapy for the patient. Among ANA, isolated anti-DFS70 antibodies represent a potentially important biomarker that can be clinically used to discriminate AARD from non-AARD patients in ANA IIF positive individuals. Therefore, their presence may avoid unnecessary follow-up testing and referrals. In our study, we investigated if the implementation of a new ANA workup algorithm allowing for the identification of anti-DFS70 antibodies is cost-effective through the reduction of both unnecessary follow-up testing and outpatient clinic visits generated by the clinical suspicion of a potential AARD. None of the 181 patients included with a positive monospecific anti-DFS70 antibody result developed SARD during the follow-up period of 10 years. The reduction in number of tests after ANA and anti-DFS70 positive results was significant for anti-ENA (230 vs. 114 tests; p < 0.001) and anti-dsDNA antibodies (448 vs. 114 tests; p < 0.001). In addition, the outpatient clinic visits decreased by 70 % (p < 0.001). In total, the adoption of the new algorithm including anti-DFS70 antibody testing resulted in a cost saving of 60869.53 € for this pilot study. In conclusion, the use of anti-DFS70 antibodies was clearly cost-efficient in our setting.

Genomic prediction of celiac disease targeting HLA-positive individuals.

BackgroundGenomic prediction aims to leverage genome-wide genetic data towards better disease diagnostics and risk scores. We have previously published a genomic risk score (GRS) for celiac disease (CD), a common and highly heritable autoimmune disease, which differentiates between CD cases and population-based controls at a clinically-relevant predictive level, improving upon other gene-based approaches. HLA risk haplotypes, particularly HLA-DQ2.5, are necessary but not sufficient for CD, with at least one HLA risk haplotype present in up to half of most Caucasian populations. Here, we assess a genomic prediction strategy that specifically targets this common genetic susceptibility subtype, utilizing a supervised learning procedure for CD that leverages known HLA-DQ2.5 risk.MethodsUsing L1/L2-regularized support-vector machines trained on large European case-control datasets, we constructed novel CD GRSs specific to individuals with HLA-DQ2.5 risk haplotypes (GRS-DQ2.5) and compared them with the predictive power of the existing CD GRS (GRS14) as well as two haplotype-based approaches, externally validating the results in a North American case-control study.ResultsConsistent with previous observations, both the existing GRS14 and the GRS-DQ2.5 had better predictive performance than the HLA haplotype approaches. GRS-DQ2.5 models, based on directly genotyped or imputed markers, achieved similar levels of predictive performance (AUC = 0.718-0.73), which were substantially higher than those obtained from the DQ2.5 zygosity alone (AUC = 0.558), the HLA risk haplotype method (AUC = 0.634), or the generic GRS14 (AUC = 0.679). In a screening model of at-risk individuals, the GRS-DQ2.5 lowered the number of unnecessary follow-up tests for CD across most sensitivity levels. Relative to a baseline implicating all DQ2.5-positive individuals for follow-up, the GRS-DQ2.5 resulted in a net saving of 2.2 unnecessary follow-up tests for each justified test while still capturing 90 % of DQ2.5-positive CD cases.ConclusionsGenomic risk scores for CD that target genetically at-risk sub-groups improve predictive performance beyond traditional approaches and may represent a useful strategy for prioritizing individuals at increased risk of disease, thus potentially reducing unnecessary follow-up diagnostic tests.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0196-5) contains supplementary material, which is available to authorized users.

Newborn Blood Spot Screening for Sickle Cell Disease by Using Tandem Mass Spectrometry: Implementation of a Protocol to Identify Only the Disease States of Sickle Cell Disease

The currently recommended technologies of HPLC and isoelectric focusing for newborn blood spot screening for sickle cell disease (SCD) identify both the disease and carrier states, resulting in large numbers of infants being followed up unnecessarily. Analysis of blood spot tryptic peptides performed by using tandem mass spectrometry (MS/MS) is an alternative technology to detect hemoglobin (Hb) variant disorders. We analyzed 2154 residual newborn blood spots and 675 newborn blood spots from infants with Hb variants by using MS/MS after trypsin digestion. Screening cutoffs were developed by using the ratio between the variant peptide-to-wild-type peptide abundance for HbS, C, D(Punjab), O(Arab), Lepore, and E peptides. A postanalytical data analysis protocol was developed using these cutoffs to detect only the disease states of SCD and not to identify carrier states. A parallel study of 13 249 newborn blood spots from a high-prevalence SCD area were analyzed by both MS/MS and HPLC. Screening cutoffs developed distinguished the infants with the disease states of SCD, infants who were carriers of SCD, and infants with normal Hb. In the parallel study no false-negative results were identified, and all clinically relevant cases were correctly identified using the MS/MS protocol. Unblinding the data revealed a total of 328 carrier infants that were successfully excluded by the protocol. The screening protocol developed correctly identified infants with the disease states of SCD. Furthermore, large numbers of sickle cell carrier infants were successfully not identified, thereby avoiding unnecessary follow-up testing and referral for genetic counseling.

Can automated alerts within computerized physician order entry improve compliance with laboratory practice guidelines for ordering Pap tests?

Background: The electronic health record (EHR) provides opportunity to improve health and enhance appropriate test utilization through decision support. Electronic alerts in the order entry system can guide test use. Few published reports have assessed the impact of automated alerts on compliance of Pap ordering with published screening guidelines. Methods: Programming rules for Pap test ordering were developed within the EHR (Epic, Madison, WI) of the University of California, Davis Health System using American College of Obstetrics and Gynecology's 2009 guidelines and implemented in primary care clinics in 2010. Alerts discouraged Pap orders in women <21 and >71 years and displayed when an order was initiated. Providers were not prevented from placing an order. Results were measured during four calendar periods: (1) pre-alert (baseline) (July 2010 to June 2011), (2) post alert (alerts on) (July 2011 to December 2011), (3) inadvertent alert turn-off (“glitch”) (January 2012 to December 2012), (5) post-glitch (alerts re-instated) (1/2013-7/2013). Metrics used to measure alert impact were between time and period seasonally adjusted relative frequency ratios. Results: Alerts were most effective in the <21 year old age group. During the baseline period 2.7 Pap tests were order in patients less than age 21 for every 100 Paps in those 21-71 years of age. This relative frequency decreased to 1.7 in the post-alert period and 1.4 during the glitch, with an even greater decline to 0.8 post-glitch when alerts were reinstated. Less impact was observed in the >70 year old group where the baseline relative frequency was 2.4 and declined to 2.1 post-alert, remained stable at 2.0 during the glitch period, and declined again to 1.7 post-glitch when alerts were reinstated. This likely reflects inclusion of women with a history of abnormal Pap tests for whom continued Pap testing is indicated, as well as reluctance by providers and patients to accept discontinuation of Pap testing for women with a history of normal Pap results. In both age groups, decreases in ordering were greatest when the alerts were functioning, indicating that the alerts had an effect beyond the influences of the environment. Conclusions: Discouraging alerts can impact ordering of Pap tests and improve compliance with established guidelines, thus avoiding unnecessary follow-up tests that can create potential patient harm and unnecessary expense. Alerts represent a potential model to address utilization of other lab tests. Longer study intervals are necessary to determine if provider compliance is maintained.

Hepatocellular Carcinoma Surveillance In Hepatitis C Patients: How Are We Doing?

Purpose: In the U.S., hepatitis C virus (HCV) is the number one cause of death from liver disease and the number one indication for liver transplantation. Those with HCV are at increased risk for hepatocellular carcinoma (HCC), the ninth leading cause of cancer-related death in the U.S. The current guideline from the American Association for the Study of Liver Diseases (AASLD) for HCC surveillance in HCV patients is performance of abdominal ultrasound every 6 months in HCV cirrhosis patients only. As of 2010, the AASLD no longer recommends serum alpha fetoprotein (AFP) testing as an HCC screening tool. We examined whether we are following HCC screening guidelines in the setting of the outpatient hepatology clinic. Methods: A systematic chart review was performed. Using a random date generator, patient charts were selected from hepatology clinic days. Only mono-infected patients with HCV were included. Patients who were co-infected with hepatitis B or HIV, had another liver diagnosis, were post-transplant, and/or required abdominal imaging for other clinical reasons were excluded. An appropriate screening interval was defined as 6 +/- 2 months (4 to 8 months). Cirrhotic patients were identified by use of the term “cirrhosis” in clinic notes only. Results: Fifty-three patients met the inclusion criteria over 8 days sampled. Of these 53 patients, 16 were identifi ed as cirrhotic, and 37 as non-cirrhotic. All of the 16 cirrhotic patients (100%) had imaging; however, seven (43.8%) were imaged less frequently than the defined interval, and 11 (68.8%) had serum AFP levels drawn. Of the 37 non-cirrhotic patients, 23 (62.2%) had imaging, and 26 (70.3%) had serum AFP levels drawn. Conclusion: Patients with non-cirrhotic HCV are likely being over-screened for HCC in the clinic setting. Additionally, serum AFP levels continue to be used for surveillance, even though these have been dropped from the guidelines. Over-screening with either imaging or serum AFP may account for inappropriate allocation of healthcare dollars and increased morbidity in patients undergoing unnecessary follow-up testing, such as CT scans. More thorough investigation of the non-cirrhotic patients may be necessary, as these patients may have “advanced fibrosis,” and thus qualify for screening under European Association for the Study of the Liver (EASL) guidelines. All patients with HCV cirrhosis are receiving imaging surveillance, but some less frequently than recommended, increasing the risk of advanced-stage HCC diagnosis. Administrative practices may need to be implemented to ensure strict follow-up with HCV cirrhosis patients. Further investigation is recommended to examine if some or all of our findings are prevalent in other hepatology clinics nationwide.

The Clinical Usefulness of Nuclear Matrix Protein-22 in Patients with End-Stage Renal Disease and Microscopic Hematuria

Objectives: To evaluate the sensitivity, specificity, and false-positive rate of the nuclear matrix protein-22 (NMP22) test in patients with end-stage renal disease (ESRD) and microscopic hematuria in order to avoid unnecessary follow-up tests for patients with false-positive NMP22 test results. Patients and Methods: Patients with ESRD were screened for microscopic hematuria as part of the pre-transplant workup. Patients with documented microscopic hematuria underwent workup as recommended by the American Urological Association. Results: Between January 2006 and April 2012, 277 patients with ESRD were referred to the Department of Urology for pre-transplant evaluation. Fifty-seven (22.6%) patients were found to have microscopic hematuria and underwent further testing. Nineteen (33.3%) patients demonstrated a positive NMP22 test result and 38 (66.7%) had a negative NMP22 test result. The false-positive rate was 32.7%. The sensitivity and specificity of the NMP22 test in this patient population were 50% and 67%, respectively. The positive predictive value of the test was 52.6% and the negative predictive value 97.3%. Especially noteworthy, the two detected transitional cell cancers of the urinary bladder were both demonstrated during cystoscopy, independent of their NMP22 or urine cytology test result. Conclusions: Our study revealed a significantly increased NMP22 test false-positive rate, low sensitivity, and specificity in the setting of high prevalence of microscopic hematuria, proteinuria, and low glomerular filtration rate in patients with ESRD. Therefore, cystoscopy remains the gold standard for patients with ESRD and microscopic hematuria for pre-transplant evaluation.

Therapeutic Monoclonal Antibody Interference with Serum Protein Electrophoresis Testing

AbstractAbstract 5025 Background and objectives:Serum protein electrophoresis (SPE) is widely used for the detection and surveillance of patients with plasma cell dyscrasias. This study was initiated following the detection of a new IgG heavy-chain immunoglobulin in a 51-year old female patient with a known history of IgDk multiple myeloma. The laboratory finding was unusual because of the rarity of an apparent IgG heavy-chain gammopathy in combination with an IgDk as well as a low quantitative serum IgG of 255 mg/dL (reference interval 600–1700). Interference was suspected and after contacting the treating physician it was established that the patient was enrolled in a phase II clinical trial with the monoclonal antibody Situximab (Centocor, Inc., Malvern, PA, USA) in combination with dexamethasone. Siltuximab is a high affinity antibody to human interleukin-6 (IL-6) currently used in clinical trials for the treatment of a number of malignancies, including multiple myeloma. The objectives of this study were to determine if monoclonal immunoglobulin therapies interfere with SPE testing and commonly used immunoassays. Methods:Siltuximab was obtained from the manufacturer and tested as an interferent using two different SPE platforms: Capillarys II (Sebia, USA) and Hydrasys (Sebia, USA). Siltuximab was analyzed alone or spiked into normal reference sera at concentrations between 50–600 mcg/mL to reflect the reported range of therapeutic circulating drug concentrations. We also examined additional monoclonal therapies at their reported mean peak serum drug concentrations. The therapies tested represented both chimeric human-mouse immunoglobulins (Rituximab, Siltuximab, Infliximab, Cetuximab) and humanized antibodies (Trastuzumab, Bevacizumab, Adalimumab). We also tested the effect of Situximab on a variety of automated serum immunoassays including hCG, iPTH, troponin T (Roche Diagnostics), cortisol, Hs-CRP, PSA, RF, and TSH (Ortho Clinical Diagnostics). Results:Siltuximab was evident as an IgGk monoclonal protein at a threshold of 100 mcg/mL and detected by all methods tested including capillary electrophoresis, immunosubtraction, agarose gel electrophoresis, and immunofixation (IFE). We also tested other widely prescribed monoclonal therapies at their reported mean peak serum drug concentrations: Rituximab (Rituxan), Trastuzumab (Herceptin), Bevacizumab (Avastin), Infliximab (Remicade), Cetuximab (Erbitux), and Adalimumab (Humira). Each drug was readily detected using IFE as an IgGk monoclonal protein (Fig 1A). Review of immunofixation results from 13 additional patients receiving Siltuximab revealed a discrete IgGk monoclonal protein corresponding to the migration of the drug in 11/13 patients (4 examples are shown in Fig 1B). In the other two cases, endogenous IgGk monoclonal immunoglobulins overlapped with the electrophoretic patterns of Siltuximab making them indistinguishable. We therefore tested two different approaches to cope with interference from monoclonal therapies: 1) adsorption of drug with specific antisera and 2) patient testing after allowing time for drug clearance. Pre-incubation of Siltuximab with anti-drug antibodies shifted the drug electrophoretic pattern such that it could potentially be differentiated from endogenous monoclonal proteins. We also observed that Siltuximab was undetectable by IFE in patients 3–4 months after cessation of therapy. This time period corresponds to approximately 5 half-lives (median half-life of siltuximab is 17.8 days). We observed no effect (<5% bias) from monoclonal therapies in commonly used immunoassays (hCG, PTH, troponin T, cortisol, Hs-CRP, PSA, RF, TSH) or quantitative immunoglobulin tests (IgG, IgA, IgM). Conclusions:Interference of monoclonal antibody therapies may be of clinical significance in patients being investigated or monitored for plasma cell dyscrasias. Individuals receiving these therapies may be subjected to unnecessary follow-up testing and patients with an IgGk gammopathy may be misconstrued as having recurrent or resistant disease. This study highlights that the possibility of false positive testing on IFE needs to be considered given the increasing use of these agents in clinical practice. Pre-incubation with anti-drug antibodies or testing after clearance of the therapeutic immunoglobulins can help clarify concerns of monoclonal therapy interference with IFE testing. [Display omitted] Disclosures:Voorhees:Millennium Pharmaceuticals: Speakers Bureau; Celgene: Speakers Bureau.

Direct-to-consumer genetic testing: more questions than benefits?

A plethora of genetic tests for susceptibility to common complex disorders have made their way onto the market. Groceries, clothing, hardware equipment, plane tickets and, now, even genetic tests can be ordered directly over the internet, from the comfort of your own home, without ever seeing a physician. Is this simply a natural progression, following in the footsteps of home pregnancy tests and blood-pressure monitors, which many people would admit do fulfill a certain niche and accomplish a lot of good for health-conscious consumers? After all, genetic testing is at the root of personalized medicine within the context of specific drug responses (pharmacogenetics). There are examples of genetic variants that do have a significant and clinically relevant effect on drug response; therefore, testing for them can lead to more efficient and cost–effective treatments [1]. However, there are many more examples with questionable validity and usefulness, so this begs the question: do direct-to-consumer (DTC) genetic services, which allow consumers to completely bypass the traditional healthcare system, do more harm than good? Direct-to-consumer genetic testing can be understood as including two related aspects: first, the advertising of genetic tests directly to consumers; and second, the direct access or ordering of genetic tests without the intermediate of a healthcare professional [2]. Although both aspects are equally important and do raise important ethical issues, they differ sufficiently to warrant separate analyses. This editorial will focus solely on DTC access to genetic testing. Other publications have tackled the issue of advertising [3,4]. Over 1100 genetic tests are available clinically and several hundreds are available in research settings. Although most genetic tests are still only available through a healthcare provider, a growing number of tests

The Incidentalome

GENOMIC MEDICINE IS POISED TO OFFER A BROAD ARray of new genome-scale screening tests. However, these tests may lead to a phenomenon in which multiple abnormal genomic findings are discovered, analogous to the “incidentalomas” that are often discovered in radiological studies. If practitioners pursue these unexpected genomic findings without thought, there may be disastrous consequences. First, physicians will be overwhelmed by the complexity of pursuing unexpected genomic measurements. Second, patients will be subjected to unnecessary follow-up tests, causing additional morbidity. Third, the cost of genomic medicine will increase substantially with little benefit to patients or physicians (but with great financial benefits to the genomic testing industry), thus throwing the overall societal benefit of genomebased medicine into question. In this article, we discuss the basis for these concerns and suggest several steps that can be taken to help avoid these substantive risks to the practice of genomically personalized medicine.

Administrative change and diagnostic test use. The effect of eliminating standing orders.

In recent years the utilization of diagnostic tests has steadily increased, prompting concerns for the rising costs of routine testing.1-6 Much attention has focused on the collective expenses of routine tests, the so-called little ticket technologies frequently used by physicians.7 Some of these tests may not be indicated, may not provide any useful information, or may lead to unnecessary duplication.8'9 Increased testing may lead to false-positive tests and thus to even more unnecessary follow-up testing. Different strategies of altering physicians' practice patterns have been explored. These include education, feedback, participation, financial rewards and penalties, and administrative changes. We studied the effects of an administrative change that limited physicians' ability to order routine diagnostic tests.