Harvey W. Kaufman

National Assessment of Warfarin Anticoagulation Therapy for Stroke Prevention in Atrial Fibrillation

Background— Anticoagulation control with warfarin, as assessed by the international normalized ratio (INR), is challenging. Time in the therapeutic range has been inversely correlated with major hemorrhage, thrombosis, and mortality. Quest Diagnostics offers standardized INR laboratory testing services to approximately half of US physician practices. To inform national stroke prevention strategies, we evaluated anticoagulation control in office-based community practices. Methods and Results— We selected individuals with ≥2 months of INR data, INR results of >1.2, and an ICD-9 diagnosis code of atrial fibrillation. Frequency of INR testing and time in the therapeutic range were analyzed by age, sex, length of testing period, number of referred patients per provider, and median household income (based on home ZIP code). We identified 138 319 individuals referred by 37 939 physicians, yielding a total of 2 683 674 INR results. Patients had a mean age of 74 years; 81% were ≥65 years of age, and 55% were ≥75 years of age. The mean time in the therapeutic range was 53.7% overall and improved with time on treatment, increasing from 47.6% for patients with <6 months of testing to 57.5% for those with ≥6 months of testing (P<0.0001). The number of patients tested per physician practice was positively associated with time in the therapeutic range. Younger age, female sex, and lower income were also independently associated with poorer anticoagulant control. Conclusion— This study demonstrates widespread suboptimal anticoagulation control, suggesting an urgent need to improve oral anticoagulation care for most patient segments in the United States.

Vitamin D May Not Improve Lipid Levels: A Serial Clinical Laboratory Data Study

Background— Vitamin D deficiency is highly prevalent and is associated with dyslipidemia and cardiovascular disease. The impact of correcting vitamin D deficiency on blood lipids, strong cardiovascular disease prognostic factors, is unknown. Methods and Results— To determine relationships between 25-hydroxyvitamin D levels and lipids, we analyzed 4.06 million deidentified patient laboratory test results from September 2009 through February 2011. We performed a cross-sectional study of this population to determine associations between 25-hydroxyvitamin D levels and lipids across clinically defined strata. We also conducted a retrospective cohort study of vitamin D deficient patients to investigate how changes in 25-hydroxyvitamin D levels relate to changes in lipid levels. After exclusions, 107 811 patients with serial testing were selected for cross-sectional analysis. Compared with vitamin D deficient patients (<20 ng/mL), those with optimal levels (≥30 ng/mL) had lower mean total cholesterol (−1.9 mg/dL; 95% confidence interval [95% CI], −1.2 to −2.7; P<0.0001), lower low-density lipoprotein cholesterol (−5.2 mg/dL; 95% CI, −4.5 to −5.8; P<0.0001), higher high-density lipoprotein cholesterol (4.8 mg/dL; 95% CI, 4.5–5.0; P<0.0001), and lower triglycerides (−7.5 mg/dL; 95% CI, −6.2 to −8.7; P<0.0001). For the retrospective cohort analysis, raising vitamin D levels from <20 to ≥30 ng/mL (n=6260), compared with remaining at <20 ng/mL (n=2332), was associated with a mean increase in total cholesterol (0.77 mg/dL; 95% CI, 0.18–1.36; P=0.01) and high-density lipoprotein cholesterol (0.42 mg/dL; 95% CI, 0.08–0.76; P=0.02) but nonsignificant changes in low-density lipoprotein cholesterol (0.32 mg/dL; 95% CI, −0.01 to 0.66; P=0.06) and triglycerides (0.04 mg/dL; 95% CI, −2.16 to 2.23 mg/dL; P=0.97). Conclusions— Although vitamin D deficiency is associated with an unfavorable lipid profile in cross-sectional analyses, correcting for a deficiency might not translate into clinically meaningful changes in lipid concentrations; however, data from intervention trials are required to confirm these findings.Background— Vitamin D deficiency is highly prevalent and is associated with dyslipidemia and cardiovascular disease. The impact of correcting vitamin D deficiency on blood lipids, strong cardiovascular disease prognostic factors, is unknown. Methods and Results— To determine relationships between 25-hydroxyvitamin D levels and lipids, we analyzed 4.06 million deidentified patient laboratory test results from September 2009 through February 2011. We performed a cross-sectional study of this population to determine associations between 25-hydroxyvitamin D levels and lipids across clinically defined strata. We also conducted a retrospective cohort study of vitamin D deficient patients to investigate how changes in 25-hydroxyvitamin D levels relate to changes in lipid levels. After exclusions, 107 811 patients with serial testing were selected for cross-sectional analysis. Compared with vitamin D deficient patients (<20 ng/mL), those with optimal levels (≥30 ng/mL) had lower mean total cholesterol (−1.9 mg/dL; 95% confidence interval [95% CI], −1.2 to −2.7; P <0.0001), lower low-density lipoprotein cholesterol (−5.2 mg/dL; 95% CI, −4.5 to −5.8; P <0.0001), higher high-density lipoprotein cholesterol (4.8 mg/dL; 95% CI, 4.5–5.0; P <0.0001), and lower triglycerides (−7.5 mg/dL; 95% CI, −6.2 to −8.7; P <0.0001). For the retrospective cohort analysis, raising vitamin D levels from <20 to ≥30 ng/mL (n=6260), compared with remaining at <20 ng/mL (n=2332), was associated with a mean increase in total cholesterol (0.77 mg/dL; 95% CI, 0.18–1.36; P =0.01) and high-density lipoprotein cholesterol (0.42 mg/dL; 95% CI, 0.08–0.76; P =0.02) but nonsignificant changes in low-density lipoprotein cholesterol (0.32 mg/dL; 95% CI, −0.01 to 0.66; P =0.06) and triglycerides (0.04 mg/dL; 95% CI, −2.16 to 2.23 mg/dL; P =0.97). Conclusions— Although vitamin D deficiency is associated with an unfavorable lipid profile in cross-sectional analyses, correcting for a deficiency might not translate into clinically meaningful changes in lipid concentrations; however, data from intervention trials are required to confirm these findings. # Clinical Perspective {#article-title-39}

National Status of Testing for Hypothyroidism during Pregnancy and Postpartum

CONTEXT Hypothyroidism, overt or subclinical, is associated with adverse outcomes for pregnant women and their offspring. Knowledge of current national thyroid testing rates and positivity during pregnancy is limited. OBJECTIVE The aim of the study was to estimate thyroid testing rate and positivity during pregnancy and postpartum, including testing and positivity rates of thyroperoxidase antibody (TPO Ab) and free T(4) tests in pregnant women with elevated TSH levels (hypothyroid), and in pregnant women having TSH within range (euthyroid). DESIGN AND SETTING Records from a large, national sample of pregnant women screened from June 2005 through May 2008 were examined. PARTICIPANTS The study included 502,036 pregnant women, for whom gestational age information was available. MAIN MEASURES Testing rates and the prevalence of hypothyroidism during pregnancy and postpartum were measured using assay-specific, trimester-specific reference intervals. Screening and positivity rates of TPO Ab and free T(4) tests were also measured. RESULTS Of women ages 18 to 40 yr, 23% (117,892 of 502,036) were tested for gestational hypothyroidism (defined as both subclinical and overt hypothyroidism). Of these, 15.5% (18,291 of 117,892) tested positive for gestational hypothyroidism. Twenty-four percent (22,650 of 93,312) of women with TSH within range and 33% (6,072 of 18,291) of women with elevated TSH were also tested for gestational hypothyroxinemia. Gestational hypothyroxinemia was seen in 0.2% (47 of 22,650) of the tested women with TSH within range and was seen in 2.4% (144 of 6,072) of the tested women having elevated TSH; 0.3% (276 of 93,312) of women with TSH within range received a TPO Ab test, and of these, 15% (41 of 276) tested positive; 0.66% (120 of 18,291) of women with elevated TSH received a TPO Ab test, and of these, 65% (78 of 120) tested positive. Only 20.7% (1873 of 9063) of hypothyroid women received thyroid screening within 6 months postpartum; of these, 11.5% (215 of 1873) were diagnosed with postpartum hypothyroidism. CONCLUSION Gestational hypothyroidism is more common than generally acknowledged. Testing is not common, and test selection is variable. There is a low rate of postpartum follow-up.

Temporal Relationship between Vitamin D Status and Parathyroid Hormone in the United States

Background Interpretation of parathyroid hormone (iPTH) requires knowledge of vitamin D status that is influenced by season. Objective Characterize the temporal relationship between 25-hydroxyvitamin D3 levels [25(OH)D3] and intact iPTH for several seasons, by gender and latitude in the U.S. and relate 25-hydrovitamin D2 [25(OH)D2] levels with PTH levels and total 25(OH)D levels. Method We retrospectively determined population weekly-mean concentrations of unpaired [25(OH)D2 and 25(OH)D3] and iPTH using 3.8 million laboratory results of adults. The 25(OH)D3 and iPTH distributions were normalized and the means fit with a sinusoidal function for both gender and latitudes: North >40, Central 32–40 and South <32 degrees. We analyzed PTH and total 25(OH)D separately in samples with detectable 25(OH)D2 (≥4 ng/mL). Findings Seasonal variation was observed for all genders and latitudes. 25(OH)D3 peaks occurred in September and troughs in March. iPTH levels showed an inverted pattern of peaks and troughs relative to 25(OH)D3, with a delay of 4 weeks. Vitamin D deficiency and insufficiency was common (33% <20 ng/mL; 60% <30 ng/mL) as was elevated iPTH levels (33%>65 pg/mL). The percentage of patients deficient in 25(OH)D3 seasonally varied from 21% to 48% and the percentage with elevated iPTH reciprocally varied from 28% to 38%. Patients with detectable 25(OH)D2 had higher PTH levels and 57% of the samples with a total 25(OH)D > 50 ng/mL had detectable 25(OH)D2. Interpretation 25(OH)D3 and iPTH levels vary in a sinusoidal pattern throughout the year, even in vitamin D2 treated patients; 25(OH)D3, being higher in the summer and lower in the winter months, with iPTH showing the reverse pattern. A large percentage of the tested population showed vitamin D deficiency and secondary hyperparathyroidism. These observations held across three latitudinal regions, both genders, multiple-years, and in the presence or absence of detectable 25(OH)D2, and thus are applicable for patient care.

Gaps in diabetes screening during pregnancy and postpartum.

OBJECTIVE: To estimate the screening rate and prevalence of gestational diabetes mellitus (GDM) and the screening rate and prevalence of postpartum diabetes, in a large, national sample of pregnant women. We also estimated the potential effects of the new International Association of Diabetes and Pregnancy Study Groups recommendations, which replace the 100-g oral glucose tolerance test (OGTT) with the 75-g OGTT, on GDM prevalence and gestational plasma glucose testing practices. METHODS: We identified pregnant women who used the laboratory services of Quest Diagnostics and who were screened for GDM and were tested postpartum. Gestational diabetes mellitus prevalence was calculated according to the current American Diabetes Association/ Carpenter-Coustan criteria, and the new International Association of Diabetes and Pregnancy Study Groups criteria. RESULTS: Sixty-eight percent (632,820/924,873) of pregnant women aged 25 to 40 (ie, those not in a low-risk age group) who utilized the services of Quest Diagnostics during this study were screened for GDM. Of the entire adult pregnant population (ages 18–40) who received GDM screening, 5% (40,955/842,993) had positive test results under the current criteria. Nineteen percent (4,486/23,299) of those with GDM received postpartum diabetes testing within a 6-month period. Ninety percent (148,749/166,085) of all confirmatory GDM tests performed on pregnant women at Quest Diagnostics were the 100-g OGTT. The number of women with GDM after receiving the 75-g OGTT would have doubled under the International Association of Diabetes and Pregnancy Study Groups criteria. CONCLUSION: Many women may not be receiving GDM screening during pregnancy. Postpartum diabetes screening rates after pregnancy remain low. Adoption of the new International Association of Diabetes and Pregnancy Study Groups criteria would require a significant change in current clinical practice. LEVEL OF EVIDENCE: III

Surge in Newly Identified Diabetes Among Medicaid Patients in 2014 Within Medicaid Expansion States Under the Affordable Care Act

OBJECTIVE Twenty-six states and the District of Columbia expanded Medicaid in January 2014 pursuant to the Affordable Care Act (ACA); 24 states did not. This created an opportunity to examine the impact of Medicaid expansion on the number of Medicaid patients with newly identified diabetes among enrollees (19–64 years of age) who had laboratory testing through Quest Diagnostics. RESEARCH DESIGN AND METHODS Newly identified diabetes was defined as an ICD-9 diagnosis code of 250.x (diabetes) or hemoglobin A1c of >6.4% (46 mmol/mol) within the first 6 months of a calendar year and the absence of both in the preceding calendar year within our data repository. RESULTS We identified 215,398 and 218,890 patients who met our definition of newly diagnosed diabetes within the first 6 months of 2013 (control period) and 2014 (study period), respectively (a 1.6% increase). We identified 26,237 Medicaid-enrolled patients with new diabetes in the control period vs. 29,673 in the study period: an increase of 13%. The number of Medicaid-enrolled patients with newly identified diabetes increased by 23% (14,625 vs. 18,020 patients) in the 26 states (and District of Columbia) that expanded Medicaid compared with an increase of 0.4% (11,612 vs. 11,653 patients) in the 24 states that did not expand Medicaid during this period. Similar differences were observed in younger and older adults and for both men and women. CONCLUSIONS This study suggests that in the states that expanded Medicaid under the ACA, an increased number of Medicaid patients with diabetes are being diagnosed and treated earlier. This could be anticipated to lead to better long-term outcomes.

Blood Cholesterol Trends 2001–2011 in the United States: Analysis of 105 Million Patient Records

Objectives We report annual trends in low density lipoprotein cholesterol (LDL-C) from an in-care patient population of nearly 105 million adults across the United States (U.S.), from 2001 through 2011. Background Average blood cholesterol values have declined in the U.S. since at least 1960. The National Health and Nutrition Examination Survey (NHANES) reported declining blood cholesterol values from 1999 through 2010. In the absence of more recent published data, we examined LDL-C values from a single clinical laboratory database to determine whether these values continued to decline through 2011. Methods and Results We extracted almost 247 million LDL-C results from nearly 105 million adults who received diagnostic testing from a single national clinical laboratory. Annual age-adjusted mean LDL-C values were calculated, and analyzed by gender. Piecewise regression analysis of the total study population indicates a breakpoint, or change in slope, in the years following 2008 (F = 163.13; p<0.05). Between 2001 and 2008, the average rate of annual decline was −2.05 mg/dL (95% CI [−2.35, −1.75]). After 2008, mean LDL-C levels flattened out, with a slope not statistically different from zero (slope = −0.10 mg/dL/year; 95% CI [−1.46, 1.26]). This stabilization was observed in both genders and all age ranges, and was also reflected in the percentage of results in low- and high-risk categories. Conclusions The trends reported suggest historical progress in decreasing LDL-C levels, observed from 2001–2008, may have stalled in recent years. Further research is needed to determine the cause of the observed trends and develop new strategies to reduce lipid-based cardiovascular risk further.

Chlamydial and gonococcal testing during pregnancy in the United States

OBJECTIVE The objective of the study was to estimate the rates of testing, prevalence, and follow-up testing for chlamydial and gonococcal infection in a nationally based population that is comparable with the US pregnant population in terms of age and race. STUDY DESIGN We extracted laboratory results for 1,293,423 pregnant women tested over a 3-year period. RESULTS During pregnancy, 59% (761,315 of 1,293,423) and 57% (730,796 of 1,293,423) of women were tested at least once for Chlamydia trachomatis or for Neisseria gonorrhoeae, respectively. Of those women tested, 3.5% (26,437 of 761,315) and 0.6% (4605 of 730,796) tested positive for chlamydial and gonococcal infection, respectively, at least once during pregnancy. Of those women who were initially positive for the given infection, 78% (16,039 of 20,489) and 76% (2610 of 3435) were retested, of whom 6.0% (969 of 16,039) and 3.8% (100 of 2610) were positive on their last prenatal test for C trachomatis and N gonorrhoeae, respectively. CONCLUSION Many pregnant women are not tested for C trachomatis and N gonorrhoeae despite recommendations to test. Follow-up testing to monitor the effectiveness of treatment is also not always performed.

Value of Laboratory Tests in Employer-Sponsored Health Risk Assessments for Newly Identifying Health Conditions: Analysis of 52,270 Participants

Background Employer-sponsored health risk assessments (HRA) may include laboratory tests to provide evidence of disease and disease risks for common medical conditions. We evaluated the ability of HRA-laboratory testing to provide new disease-risk information to participants. Methodology/Principal Findings We performed a cross-sectional analysis of HRA-laboratory results for participating adult employees and their eligible spouses or their domestic partners, focusing on three common health conditions: hyperlipidemia, diabetes mellitus, and chronic kidney disease. HRA with laboratory results of 52,270 first-time participants were analyzed. Nearly all participants had access to health insurance coverage. Twenty-four percent (12,392) self-reported one or more of these medical conditions: 21.1% (11,017) self-identified as having hyperlipidemia, 4.7% (2,479) self-identified as having diabetes, and 0.7% (352) self-identified as having chronic kidney disease. Overall, 36% (n = 18,540) of participants had laboratory evidence of at least one medical condition newly identified: 30.7% (16,032) had laboratory evidence of hyperlipidemia identified, 1.9% (984) had laboratory evidence of diabetes identified, and 5.5% (2,866) had laboratory evidence of chronic kidney disease identified. Of all participants with evidence of hyperlipidemia 59% (16,030 of 27,047), were newly identified through the HRA. Among those with evidence of diabetes 28% (984 of 3,463) were newly identified. The highest rate of newly identified disease risk was for chronic kidney disease: 89% (2,866 of 3,218) of participants with evidence of this condition had not self-reported it. Men (39%) were more likely than women (33%) to have at least one newly identified condition (p<0.0001). Among men, lower levels of educational achievement were associated with modestly higher rates of newly identified disease risk (p<0.0001); the association with educational achievement among women was unclear. Even among the youngest age range (20 to 29 year olds), nearly 1 in 4 participants (24%) had a newly identified risk for disease. Conclusions/Significance These results support the important role of employer-sponsored laboratory testing as an integral element of HRA for identifying evidence of previously undiagnosed common medical conditions in individuals of all working age ranges, regardless of educational level and gender.

Concurrent Use of Opioids and Benzodiazepines: Evaluation of Prescription Drug Monitoring by a United States Laboratory

Objectives: Recently, more than 63% of the 52,404 drug overdose deaths in the United States involved heroin and opioid pain medications. More than 30% of opioid-related deaths also involved benzodiazepines. Previous studies examining the extent of concurrent opioid and benzodiazepine use have relied on prescription data. To gain fuller insight into the extent of the concurrent use problem, we analyzed opioid and benzodiazepine prescription patterns in the context of drug testing results. Methods: All specimens from patients that were prescribed at least 1 drug and were tested for both opioids and benzodiazepines by a national reference laboratory were included. This resulted in an analytical set of 231,228 sets of test results from 144,535 patients with diverse demographic factors being tested in a variety of health care settings. Results: Laboratory test results indicated concurrent use of opioids and benzodiazepines in over 25% of patients. In 52% of test results with evidence of concurrent use, 1 drug class was prescribed and the other was non-prescribed. Nearly 1 in 5 specimens (19%) testing positive for prescribed opioids also tested positive for non-prescribed benzodiazepines. Over 15% of specimens with prescribed benzodiazepines also demonstrated non-prescribed opioid use. Conclusions: The extent of concurrent use of benzodiazepines and opioids, particularly non-prescribed use, suggests the need for more effective clinician assessment and intervention. The results support the Centers for Disease Control and Prevention opioid prescribing guidelines that drug testing occur before and periodically throughout opioid use and suggest that this testing should be extended to patients prescribed benzodiazepines as well.