Assessing Quality Control Strategies for HbA1c Measurements From a Patient Risk Perspective.

BACKGROUND: Current laboratory risk management principles emphasize the importance of assessing laboratory quality control (QC) practices in terms of the risk of patient harm. Limited practical guidance or examples on how to do this are available. METHODS: The patient risk model described in a published laboratory risk management guideline was combined with a recently reported approach to computing the predicted probability of patient harm to produce a risk management index (RMI) that compares the predicted probability of patient harm for a QC strategy to the acceptable probability of patient harm based on the expected severity of harm caused by an erroneously reported patient result. RESULTS: Measurement procedure capability and quality control performance for two instruments measuring HbA1c in a laboratory were assessed by computing the RMI for each instrument individually and for the laboratory as a whole. CONCLUSIONS: This assessment provides a concrete example of how laboratory QC practices can be directly correlated to the risk of patient harm from erroneously reported patient results.

Utilization of assay performance characteristics to estimate hemoglobin A1c result reliability.

BACKGROUND: Allowable total error (TE(a)) goals for hemoglobin (Hb) A(1c) require minimal assay imprecision and bias and implementation of a robust QC monitoring program. Here, we compare the combined influence on the risk of reporting unreliable results of TE(a) goals, a routine QC practice, and assay performance characteristics of 6 Hb A(1c) instruments across 4 academic medical centers. METHODS: The CLSI protocols EP-5 and EP-9 were applied to investigate Hb A(1c) result imprecision and bias on the Variant II Turbo and Variant II (Bio-Rad), G8 (Tosoh), Capillarys 2 Flex Piercing (Sebia), COBAS Integra 800 (Roche), and DCA Vantage (Siemens). Patient-weighted σ values and the risk of reporting unreliable Hb A(1c) results were determined for each assay at TE(a) specifications of 5%, 6%, and 7%. RESULTS: A large range of patient-weighted σ values spanning 0.5 orders of magnitude at a 6% TE(a) was observed. Although imprecision for all instruments was <3%, bias impacted the majority of the σ changes observed. Estimates for reporting unreliable results varied almost 500-fold based on analytical performance alone. CONCLUSIONS: Considerable differences in the probability of reporting unreliable Hb A(1c) results between different NGSP (formerly the National Glycohemoglobin Standardization Program)-certified platforms were observed. At a 6% TE(a), our study indicates all but the Capillarys 2 Flex Piercing requires that the maximum affordable QC be run. Risk estimates for individual laboratories' Hb A(1c) methods can be used to assess QC practices and residual risk of an unreliable Hb A(1c) result.

Comparing analytic performance criteria: evaluation of HbA1c certification criteria as an example.

BACKGROUND: Direct comparison of analytical performance criteria that utilize different statistical approaches can be problematic. We describe a mathematical approach to compare performance criteria for hemoglobin A1c (HbA1c) analysis used by the NGSP standardization program and the College of American Pathologists (CAP) to enhance consistency between the schemes. METHODS: The imprecision (CV) and bias combinations required to pass each criterion at probabilities of 0.95, 0.99 and 0.999 were calculated and used to construct contour plots to compare them. The CV/bias requirements were calculated mathematically for the 2011-2012 CAP (3/3 results within ±7% of the target) and different proposed NGSP (33/40 to 40/40 results within ±7% of the target) criteria, and using computer simulations for the existing NGSP criterion (95% confidence interval of the differences between the method and NGSP within ±0.75% HbA1c). RESULTS: Requiring 37 of 40 results to be within ±7% of the NGSP target best matched the CAP criterion at zero bias (95% chance of passing). CONCLUSIONS: The NGSP Steering Committee recommended a certification criterion of 37 of 40 results within ±7% of the NGSP (reduced to ±6% in 2014). The described evaluation approach may be useful in other situations where comparison of different performance criteria is desired.

Validating the performance of QC procedures.

A methodology for computing the maximum expected number of unreliable patient results produced because of an out-of-control condition for a given quality control strategy is presented along with strategies for changing the expected number of unreliable results produced and reported. The expected number of unreliable patient results reported before and after the last accepted quality control evaluation before the detection of an out-of-control condition are discussed and used as design criteria for quality control strategies that meet a laboratory's risk criteria.

Should I repeat my 1:2s QC rejection?

BACKGROUND: Repeating a QC that is outside 2SD from the mean (1:2s rule) appears to be a common practice. Although this form of repeat sampling is frowned on by many, the comparative power of the approach has not been formally evaluated. METHODS: We computed power functions mathematically and by computer simulation for 4 different 1:2s repeat-sampling strategies, as well as the 1:2s rule, the 1:3s rule, and 2 common QC multirules. RESULTS: The false-rejection rates for the repeat-sampling strategies were similarly low to those of the 1:3s QC rule. The error detection rates for the repeat-sampling strategies approached those of the 1:2s QC rule for moderate to large out-of-control error conditions. In most cases, the power of the repeat-sampling strategies was superior to the power of the QC multirules we evaluated. The increase in QC utilization rate ranged from 4% to 13% for the repeat-sampling strategies investigated. CONCLUSIONS: The repeat-sampling strategies provide an effective tactic to take advantage of the desirable properties of both the 1:2s and 1:3s QC rules. Additionally, the power of the repeat-sampling strategies compares favorably with the power of 2 common QC multirules. These improvements come with a modest increase in the average number of controls tested.

HPV-related nonkeratinizing squamous cell carcinoma of the oropharynx: utility of microscopic features in predicting patient outcome.

Human papilloma virus (HPV) is an etiologic agent in a subset of oropharyngeal squamous cell carcinomas (SCCs). The aim of this study was to sub-classify SCC of the oropharynx based upon histologic features into nonkeratinizing (NK) SCC, keratinizing (K) SCC, and hybrid SCC, and determine the frequency of HPV and patient survival in each group. Patients with oropharyngeal SCC with a minimum of 2 years of clinical follow-up were identified from radiation oncology databases from 1997 to 2004. All patients received either up front surgery with postoperative radiation or definitive radiation based therapy. In situ hybridization (ISH) for high-risk HPV subtypes and immunohistochemistry for p16, a protein frequently up-regulated in HPV-associated carcinomas, were performed. Overall and disease-specific survival were assessed. Of 118 cases, 46.6% were NK SCC, 24.6% K SCC and 28.8% hybrid SCC. NK SCC occurred in slightly younger patients that were more often male. It more frequently presented with lymph node metastases and was surgically resected compared to K SCC. NK SCC was significantly more likely to be HPV and p16 positive than KSCC (P < 0.001) and to have better overall and disease-specific survival (P = 0.0002; P = 0.0142, respectively). Hybrid SCC was also more likely than K SCC to be HPV and p16 positive (P = 0.003; P = 0.002, respectively) and to have better overall survival (P = 0.0105). Sub-classification of oropharyngeal SCC by histologic type provides useful clinical information. NK SCC histology strongly predicts HPV-association and better patient survival compared to K SCC. Hybrid SCC appears to have an intermediate frequency of HPV-association and patient survival.

Synaptic ultrastructural alterations anticipate the development of neuroaxonal dystrophy in sympathetic ganglia of aged and diabetic mice.

Neuroaxonal dystrophy, a distinctive axonopathy characterized by marked enlargement of distal axons, is the hallmark pathologic alteration in aged and diabetic human prevertebral sympathetic ganglia and in corresponding rodent models. Neuroaxonal dystrophy is thought to represent the abnormal outcome of cycles of synaptic degeneration and regeneration; a systematic study of identified axon terminals in aged and diabetic prevertebral ganglia, however, has not previously been performed. We examined the initial changes that develop in presynaptic and postsynaptic elements in sympathetic ganglia of aged and diabetic mice and found numerous synaptic changes involving both presynaptic and postsynaptic elements. Early alterations in presynaptic axon terminal size, vesicle content, and morphology culminate in the development of anastomosing membranous tubulovesicular aggregates, accumulation of autophagosomes, and amorphous debris that form a continuum with progressively larger classically dystrophic swellings. Dendritic changes consist of the development of swellings composed of delicate tubulovesicular elements and mitochondriopathy characterized by increased numbers of small mitochondria and, exclusively in aged ganglia, megamitochondria. These results support the hypothesis that neuroaxonal dystrophy results from progressive changes in presynaptic axon terminals that likely involve membrane dynamics and which are accompanied by distinctive changes in postsynaptic dendritic elements.

The impact of QC frequency on patient results.

The expected number of unacceptable patient results due to an undetected, malfunction--E(Nu)--can be set as a patient-based quality goal. Using the number of patients tested between QC specimens as a design parameter allows one to design QC strategies that meet specified patient-based quality goals. The QC utilization rate can be minimized in a QC design for a given E(Nu). The QC-utilization rate achievable depends on how close analytical imprecision is to the total allowable error.

Assessing the impact of the frequency of quality control testing on the quality of reported patient results.

BACKGROUND: The traditional measure used to evaluate QC performance is the probability of rejecting an analytical run that contains a critical out-of-control error condition. The probability of rejecting an analytical run, however, is not affected by changes in QC-testing frequency. A different performance measure is necessary to assess the impact of the frequency of QC testing. METHODS: I used a statistical model to define in-control and out-of-control processes, laboratory testing modes, and quality control strategies. RESULTS: The expected increase in the number of unacceptable patient results reported during the presence of an undetected out-of-control error condition is a performance measure that is affected by changes in QC-testing frequency. I derived this measure for different out-of-control error conditions and laboratory testing modes and showed that a worst-case expected increase in the number of unacceptable patient results reported can be estimated. The laboratory thus has the ability to design QC strategies that limit the expected number of unacceptable patient results reported. CONCLUSIONS: To assess the impact of the frequency of QC testing on QC performance, it is necessary to move beyond thinking in terms of the probability of accepting or rejecting analytical runs. A performance measure based on the expected increase in the number of unacceptable patient results reported has the dual advantage of objectively assessing the impact of changes in QC-testing frequency and putting focus on the quality of reported patient results rather than the quality of laboratory batches.

Use of serum FSH to identify perimenopausal women with pituitary hCG.

BACKGROUND: Human chorionic gonadotropin (hCG) tests are performed on many female patients before performing medical procedures or administering medications that may harm a fetus. hCG of pituitary origin has been shown to increase with age. Therefore, mild increases in serum hCG in an older patient can be of pituitary origin and does not necessarily indicate pregnancy. The inability to rule out pregnancy in perimenopausal women can create clinical confusion and may delay needed therapies. Our objective was to determine the diagnostic utility of serum follicle-stimulating hormone (FSH) concentrations to rule out hCG of placental origin in perimenopausal women with a low concentration of serum hCG (5.0-14.0 IU/L). METHODS: Seven testing centers performed 39 742 physician-ordered serum quantitative hCG tests over a 15-month period. From these, 100 samples from women 41-55 years of age with serum hCG concentrations 5-14 IU/L were identified. We performed FSH testing and patient chart review for each sample. RESULTS: Twenty-three patients were found to have hCG of placental origin (pregnancy, resolving abortion, or gestational trophoblastic disease), and in those cases serum FSH was 0.4-43.8 IU/L. An FSH cutoff of 45.0 IU/L identified hCG of placental origin with 100% sensitivity and 75% specificity. FSH >45 IU/L was never observed when hCG was of placental origin (negative predictive value). CONCLUSIONS: These data indicate that quantitative serum FSH can be used to rule out pregnancy and hCG of placental origin in women 41-55 years of age with mild increase in serum hCG concentrations.

Clinical and economic impact of falsely decreased calcium values caused by gadoversetamide interference.

OBJECTIVE: Gadolinium is administered as a contrast agent in MRI procedures. Two gadolinium-based contrast agents, gadodiamide and gadoversetamide, interfere with colorimetric total serum calcium methods. The purpose of this prospective observational study was to examine the incidence of calcium interference after gadoversetamide procedures, associated clinical outcomes, and costs 20 months after implementation of quality assurance and physician education programs. MATERIALS AND METHODS: Records of patients who received gadoversetamide from June 24, 2006, to October 7, 2006, were reviewed to determine if a routine calcium test had been performed after the injection. Calcium values were repeated with an alternate method that is less susceptible to gadoversetamide interference. If the difference was > or = 2.0 mg/dL or if the initial test value was < or = 7.0 mg/dL, patient charts were reviewed for any related treatment. Costs associated with this algorithm were tracked. RESULTS: The initial calcium test was performed after gadoversetamide in 766 of 3,439 instances. The alternate test was performed in 633 of 766. One hundred twenty-five of 633 (20%) showed a difference in calcium values that was > or = 0.7 mg/dL, with 16 showing differences of > or = 1.6 mg/dL. Chart review for 56 instances revealed that calcium supplements were administered in 22 of 56 around the time of gadoversetamide injection. However, none appeared to be related to the spurious hypocalcemia. The total additional cost (reagent and technologist) for following this algorithm for just over 3 months was $6,807. CONCLUSION: Approximately 20% of patients receiving gadoversetamide exhibited spurious hypocalcemia. No patients were identified who received inappropriate calcium because of this interference. This may be attributable to the quality assurance and physician education programs.

Erythropoietin and its carbamylated derivative prevent the development of experimental diabetic autonomic neuropathy in STZ-induced diabetic NOD-SCID mice.

Autonomic neuropathy is a significant diabetic complication resulting in increased morbidity and mortality. Studies of autopsied diabetic patients and several rodent models demonstrate that the neuropathologic hallmark of diabetic sympathetic autonomic neuropathy in prevertebral ganglia is the occurrence of synaptic pathology resulting in distinctive dystrophic neurites ("neuritic dystrophy"). Our prior studies show that neuritic dystrophy is reversed by exogenous IGF-I administration without altering the metabolic severity of diabetes, i.e. functioning as a neurotrophic substance. The description of erythropoietin (EPO) synergy with IGF-I function and the recent discovery of EPO's multifaceted neuroprotective role suggested it might substitute for IGF-I in treatment of diabetic autonomic neuropathy. Our current studies demonstrate EPO receptor (EPO-R) mRNA in a cDNA set prepared from NGF-maintained rat sympathetic neuron cultures which decreased with NGF deprivation, a result which demonstrates clearly that sympathetic neurons express EPO-R, a result confirmed by immunohistochemistry. Treatment of STZ-diabetic NOD-SCID mice have demonstrated a dramatic preventative effect of EPO and carbamylated EPO (CEPO, which is neuroprotective but not hematopoietic) on the development of neuritic dystrophy. Neither EPO nor CEPO had a demonstrable effect on the metabolic severity of diabetes. Our results coupled with reported salutary effects of EPO on postural hypotension in a few clinical studies of EPO-treated anemic diabetic and non-diabetic patients may reflect a primary neurotrophic effect of EPO on the sympathetic autonomic nervous system, rather than a primary hematopoietic effect. These findings may represent a major clinical advance since EPO has been widely and safely used in anemic patients due to a variety of clinical conditions.

Impact of a multidisciplinary intervention for diabetes in Eritrea.

BACKGROUND: When hemoglobin A1c (HbA1c) testing was made available to diabetic patients in the nation of Eritrea, the majority of values were markedly increased. As a result, a multidisciplinary clinical education program was instituted in Eritrea and the rate of HbA1c testing was increased to monitor progress. METHODS: In February 2003, a cooperative diabetes project was initiated in Eritrea to train diabetes educators, enhance physician education, create patient-teaching materials, and promote glucose monitoring. Two additional visits were made in 2003 and 2004. HbA1c values from January 2003 to November 2004 (n = 3606) were reviewed to assess diabetic control for the population and for a subset of individual patients (n = 350). A cohort of 209 diabetic persons were evaluated for demographics, treatment, and prevalence of complications. RESULTS: The cohort of 209 patients was 34% female and had a mean (SD) age of 50.5 (15.5) years and diabetes duration of 8.6 (6.3) years. Prevalence of hypertension was 37% and proteinuria 6%. For diabetes treatment, 59% received insulin therapy, 35% received oral agents, and 6% received nonpharmacologic treatment. HbA1c values improved significantly between the 1st 6 months of 2003 (median 10.9%) and the last 6 months of 2004 (median 8.5%; P <0.001). Individual patients in whom 2 HbA1c values were measured > or =3 months apart showed a significant mean decrease of 0.5% (P <0.001). CONCLUSIONS: Our experience suggests that the combination of sustainable upgraded laboratory services and training in clinical management leads to sustainable improvement in diabetes care in developing countries.

Evaluation of the performance of randomized versus fixed time schedules for quality control procedures.

BACKGROUND: Although minimum regulatory standards exist for determining QC testing frequency, decisions regarding when and how to run QC samples are not standardized. Most QC testing strategies test control samples at fixed time intervals, often placing the samples in the same position on an instrument during subsequent QC events and leaving large gaps of time when control samples are never run, yet patient samples are being tested. METHODS: Mathematical derivations and computer simulation were used to determine the expected waiting time between an out-of-control condition and the next scheduled QC test for various QC testing strategies that use fixed or random intervals between QC tests. RESULTS: Scheduling QC tests at fixed intervals yields an average time between the occurrence of an out-of-control error condition and the next scheduled QC test that is equal to half of the fixed time interval. This performance was the best among the QC scheduling strategies investigated. Near-optimal performance, however, was achieved by randomly selecting time intervals between QC events centered on the desired expected interval length, a method that provides variation in QC testing times throughout the day. CONCLUSIONS: If the goal is to vary QC testing times throughout the day while maintaining the shortest expected length of time between error conditions and the next scheduled QC test, then a near-optimal QC scheduling strategy combines randomly selected time intervals centered on the desired length of time between QC events with fixed time intervals.

Statistical topics in the laboratory sciences.

This chapter concerns statistical concepts and procedures that are applicable to diagnostic testing performed in the clinical laboratory. Three important laboratory issues are addressed: the estimation of analytical imprecision, the design of an effective laboratory quality control strategy, and the establishment of population reference ranges. These three topics were selected because each demonstrates a valuable statistical principle. Estimation of analytical imprecision highlights the important role of study design. Evaluating laboratory quality control strategies emphasizes the importance of choosing appropriate statistical models. The estimation of population reference ranges demonstrates that there can be many different approaches to developing good statistical estimators.

A direct comparison between lamellar body counts and fluorescent polarization methods for predicting respiratory distress syndrome.

Our objective was to directly compare the diagnostic usefulness of lamellar body counting (LBC) and the TDx-FLM II assay (Abbott Laboratories, Abbott Park, IL) for predicting respiratory distress syndrome (RDS). This was a 5-year, retrospective, cohort study. A diagnosis of RDS was given to infants who received surfactant treatment and/or required ventilator support and/or continuous positive airway pressure for more than 24 hours. There were 172 infants without RDS and 12 with RDS included in the study. By using a TDx-FLM II cutoff of 55 mg/g or more for maturity, the sensitivity was 83%, specificity was 65%, predictive value of a mature result was 98%, and predictive value of an immature result was 14%. These results were similar to LBC using a cutoff of 50,000/microL or more with sensitivity of 92%, a specificity of 60%, a predictive value of a mature result of 99%, and a predictive value of an immature result of 14%. The LBC and TDx-FLM II methods have similar clinical usefulness.