232 results on '"Klee GG"'
Search Results
2. B-type natriuretic peptide in the assessment of acute lung injury and cardiogenic pulmonary edema.
- Author
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Rana R, Vlahakis NE, Daniels CE, Jaffe AS, Klee GG, Hubmayr RD, and Gajic O
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- 2006
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3. MUC1 gene-derived glycoprotein assays for monitoring breast cancer (CA 15-3, CA 27.29, BR): are they measuring the same antigen?
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Klee GG and Schreiber WE
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- 2004
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4. Mechanisms of the age-associated deterioration in glucose tolerance: contribution of alterations in insulin secretion, action, and clearance.
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Basu R, Breda E, Oberg AL, Powell CC, Man CD, Basu A, Vittone JL, Klee GG, Arora P, Jensen MD, Toffolo G, Cobelli C, Rizza RA, Basu, Rita, Breda, Elena, Oberg, Ann L, Powell, Claudia C, Dalla Man, Chiara, Basu, Ananda, and Vittone, Janet L
- Abstract
Glucose tolerance decreases with age. For determining the cause of this decrease, 67 elderly and 21 young (70.1 +/- 0.7 vs. 23.7 +/- 0.8 years) participants ingested a mixed meal and received an intravenous injection of glucose. Fasting glucose and the glycemic response above basal were higher in the elderly than in the young participants after either meal ingestion (P < 0.001) or glucose injection (P < 0.01). Insulin action (Si), measured with the meal and intravenous glucose tolerance test models, was highly correlated (r = 0.72; P < 0.001) and lower (P
- Published
- 2003
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5. Insulin-like growth factor I, insulin-like growth factor finding protein 3, and urologic measures of benign prostatic hyperplasia.
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Roberts RO, Jacobson DJ, Girman CJ, Rhodes T, Klee GG, Lieber MM, and Jacobsen SJ
- Abstract
Laboratory studies suggest that insulin-like growth factor I (IGF-I) promotes prostatic growth. The authors evaluated the association between benign prostatic hyperplasia and IGF-I and its binding protein IGFBP-3 in community-dwelling men to determine whether this laboratory finding is manifest at the population level. Participants (n = 471) were Olmsted County, Minnesota, Caucasian males aged 40-79 years in 1990. Urologic measures were assessed from the International Prostate Symptom Score, peak urinary flow rates, prostate volume, and serum prostate-specific antigen (PSA), and serum IGF-I and IGFBP-3 levels were measured. After adjustment for age, the relative odds (odds ratios) of an abnormal urologic measure in men with high versus low serum IGF-I levels were 0.98 (95% confidence interval (CI): 0.66, 1.45) for a symptom score of >7, 1.14 (95% CI: 0.72, 1.80) for a peak urinary flow rate of <12 ml/second, 1.11 (95% CI: 0.72, 1.72) for a prostate volume of >30 ml, and 0.71 (95% CI: 0.46, 1.09) for a PSA level of >1.4 ng/ml. A low IGFBP-3 level was associated with an enlarged prostate (odds ratio = 1.72, 95% CI: 1.05, 2.82), after simultaneous adjustment for IGF-I and age, but not with other urologic measures. These data do not provide evidence for an association between benign prostatic hyperplasia and serum IGF-I. [ABSTRACT FROM AUTHOR]
- Published
- 2003
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6. Incidence of prostate cancer diagnosis in the eras before and after serum prostate-specific antigen testing.
- Author
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Jacobsen SJ, Katusic SK, Bergstralh EJ, Oesterling JE, Ohrt D, Klee GG, Chute CG, Lieber MM, Jacobsen, S J, Katusic, S K, Bergstralh, E J, Oesterling, J E, Ohrt, D, Klee, G G, Chute, C G, and Lieber, M M
- Abstract
Objective: To estimate the incidence of prostate cancer in Olmsted County, Minnesota, from 1983 through 1992 to describe the secular changes that have occurred since the introduction of serum prostate-specific antigen (PSA) testing to the community medical practice in 1987.Design: Population-based, descriptive epidemiological study with ecological and individual level comparisons over time.Study Setting: Olmsted County, Minnesota, where the Rochester Epidemiology Project provides passive surveillance of the population for health outcomes.Subjects: All 511 biopsy-proven incident cases of adenocarcinoma of the prostate diagnosed from 1983 through 1992. The community inpatient and outpatient medical records of all incident cases were reviewed to evaluate the presenting characteristics of men at the time of diagnosis.Results: The age-adjusted incidence of biopsy-proven prostate cancer increased from 64 per 100,000 person-years in 1983 to 216 per 100,000 person-years in 1992. The increase occurred primarily between 1987 and 1988 and was predominately for organ-confined tumors. The age-specific incidence increased dramatically in this same period among men aged 50 years and older. Among men aged 70 years and older, however, prostate carcinoma incidence rates declined after 1990 following the initial increase. This decline among older men contrasted with community-based estimates of PSA utilization rates, which demonstrated consistent increases since 1987 to nearly 50% of the older population in 1992.Conclusion: These results support the premise that the recent increase in prostate cancer is due in part to the increased utilization of serum PSA testing. Further, the increased incidence appears to be a transient phenomenon due to the depletion of previously undiagnosed cases from the previous pool. Finally, these data suggest that, in terms of stage at diagnosis, early detection efforts may be effective in identifying more early stage (smaller) cancers. [ABSTRACT FROM AUTHOR]- Published
- 1995
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7. Predictive properties of serum-prostate-specific antigen testing in a community-based setting.
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Jacobsen SJ, Bergstralh EJ, Guess HA, Katusic SK, Klee GG, Oesterling JE, and Lieber MM
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- 1996
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8. How sensitive is a prostate-specific antigen measurement: How sensitive does it need to be?
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Bock JL and Klee GG
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- 2004
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9. College of American Pathologists 2003 fresh frozen serum proficiency testing studies.
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Klee GG and Killeen AA
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- 2005
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10. Effects of reducing the upper limit of normal TSH values.
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Fatourechi V, Klee GG, Grebe SK, Bahn RS, Brennan MD, Hay ID, McIver B, Morris JC III, Fatourechi, Vahab, Klee, George G, Grebe, Stefan K, Bahn, Rebecca S, Brennan, Michael D, Hay, Ian D, McIver, Bryan, and Morris, John C 3rd
- Published
- 2003
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11. Effect of different glucose meter error tolerances on dosing errors during intravenous insulin administration.
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Karon BS, Deobald G, and Klee GG
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- 2008
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12. Analytic bias of thyroid function tests: analysis of a College of American Pathologists fresh frozen serum pool by 3900 clinical laboratories.
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Steele BW, Wang E, Klee GG, Thienpont LM, Soldin SJ, Sokoll LJ, Winter WE, Fuhrman SA, and Elin RJ
- Published
- 2005
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13. A comparison of human chorionic gonadotropin-related components in fresh frozen serum with the proficiency testing material used by the College of American Pathologists.
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Knight GJ, Palomaki GE, Klee GG, Schreiber WE, and Cole LA
- Published
- 2005
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14. Longitudinal changes of benign prostate-specific antigen and [-2]proprostate-specific antigen in seven years in a community-based sample of men.
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Rhodes T, Jacobson DJ, McGree ME, St Sauver JL, Girman CJ, Lieber MM, Klee GG, Demissie K, Jacobsen SJ, Rhodes, Thomas, Jacobson, Debra J, McGree, Michaela E, St Sauver, Jennifer L, Girman, Cynthia J, Lieber, Michael M, Klee, George G, Demissie, Kitaw, and Jacobsen, Steven J
- Abstract
Objective: To determine the longitudinal changes of benign prostate-specific antigen (BPSA) and [-2]proPSA and how these changes relate to the outcomes. These markers have been shown to be predictive of prostate cancer (CaP) and benign prostatic hyperplasia treatment; however, little is known about longitudinal changes in these markers.Methods: In 1990, a 25% subsample from a cohort of white men aged 40-79 years, who were randomly selected from Olmsted County, Minnesota residents, completed a detailed clinical examination. BPSA and [-2]proPSA were measured from frozen sera. The men were evaluated biennially (median follow-up 7 years; range 0-8.8). Mixed-effects regression models were used to estimate the longitudinal changes in the BPSA and [-2]proPSA levels overall and by outcomes. Spearman correlations were used to compare these changes with the baseline levels and the annualized changes in urologic measures.Results: The median and 25th and 75th percentiles annualized percent change for [-2]proPSA and BPSA was 3.7%, 2.5% and 5.2% and 7.3%, 6.8%, and 7.7%, respectively. The annualized percent change for both markers correlated with the baseline and annualized changes in PSA and prostate volume. The annualized percent change increased with increasing age decade for [-2]proPSA but not for BPSA. The rate of increase in [-2]proPSA was significantly greater for men who developed enlarged prostates (median 3.5%, 25th and 75th percentile 2.6% and 4.4%, respectively) or CaP (median 8.1%, 25th and 75th percentile 6.6% and 9.8%, respectively) compared with those who did not develop enlarged prostates (median 1.9%, 25th and 75th percentile 0.9% and 3.0%, respectively) or CaP (median 3.5%, 25th and 75th percentile 2.3% and 4.8%, respectively).Conclusion: BPSA and [-2]proPSA levels increase over time. The annualized percent change in [-2]proPSA increases with age and might be a useful predictor of CaP development. [ABSTRACT FROM AUTHOR]- Published
- 2012
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15. DHEA in elderly women and DHEA or testosterone in elderly men.
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Nair KS, Rizza RA, O'Brien P, Dhatariya K, Short KR, Nehra A, Vittone JL, Klee GG, Basu A, Basu R, Cobelli C, Toffolo G, Dalla Man C, Tindall DJ, Melton LJ III, Smith GE, Khosla S, and Jensen MD
- Published
- 2006
16. Comparison of pooled fresh frozen serum to proficiency testing material in College of American Pathologists surveys: cortisol and immunoglobulin E.
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Palmer-Toy DE, Wang E, Winter WE, Soldin SJ, Klee GG, Howanitz JH, and Elin RJ
- Published
- 2005
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17. Comparison of fresh frozen serum to proficiency testing material in College of American Pathologists surveys: alpha-fetoprotein, carcinoembryonic antigen, human chorionic gonadotropin, and prostate-specific antigen.
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Schreiber WE, Endres DB, McDowell GA, Palomaki GE, Elin RJ, Klee GG, and Wang E
- Published
- 2005
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18. Comparison of fresh frozen serum to traditional proficiency testing material in a College of American Pathologists survey for ferritin, folate, and vitamin B12.
- Author
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Bock JL, Endres DB, Elin RJ, Wang E, Rosenzweig B, and Klee GG
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- 2005
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19. Total long-term within-laboratory precision of cortisol, ferritin, thyroxine, free thyroxine, and thyroid-stimulating hormone assays based on a College of American Pathologists fresh frozen serum study: do available methods meet medical needs for precision?
- Author
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Steele BW, Wang E, Palmer-Toy DE, Killeen AA, Elin RJ, and Klee GG
- Published
- 2005
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20. Lack of association between lipoprotein(a) and coronary artery calcification in the Genetic Epidemiology Network of Arteriopathy (GENOA) study.
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Kullo IJ, Bailey KR, Bielak LF, Sheedy PF II, Klee GG, Kardia SL, Peyser PA, Boerwinkle E, Turner ST, Kullo, Iftikhar J, Bailey, Kent R, Bielak, Lawrence F, Sheedy, Patrick F 2nd, Klee, George G, Kardia, Sharon L, Peyser, Patricia A, Boerwinkle, Eric, and Turner, Stephen T
- Abstract
Objective: To investigate the relationship between lipoprotein(a) [Lp(a)] levels and the extent of coronary atherosclerosis in a cohort that consisted predominantly of hypertensive patients.Patients and Methods: Patients were ascertained through sibships that contained at least 2 individuals with essential hypertension diagnosed before the age of 60 years. The 10-year coronary heart disease (CHD) risk was estimated on the basis of the Framingham risk equation. Serum Lp(a) was measured by an immunoturbidimetric assay. Coronary artery calcification (CAC) was measured noninvasively by electron beam computed tomography and CAC score calculated using the Agatston score.Results: Patients included 765 non-Hispanic, white individuals (59% women) participating in the Genetic Epidemiology Network of Arteriopathy study. The mean +/- SD age of the patients was 62 +/- 8 years, and 77% had hypertension. The prevalence of detectable CAC was 87% in men and 60% in women. The CAC scores did not differ significantly across quintiles of Lp(a) levels in either men or women. In a multiple regression model that included conventional risk factors, Lp(a) levels were not related to CAC quantity in either sex. No significant interactions were noted between Lp(a) levels and the conventional risk factors in the prediction of CAC quantity. When stratified on the basis of the 10-year CHD risk, 26.5% of the patients were low risk (< 6%), 60.5% were intermediate risk (6%-20%), and 12.9% were high risk (> 20%). Lipoprotein(a) was not associated with CAC quantity within subgroups based on 10-year CHD risk.Conclusion: In this cohort enriched with hypertensive patients, the estimated 10-year CHD risk did not appear to modify the lack of an association between Lp(a) levels and CAC. [ABSTRACT FROM AUTHOR]- Published
- 2004
21. Factors influencing clinical decisions to initiate thyroxine therapy for patients with mildly increased serum thyrotropin (5.1-10.0 mIU/L)
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Fatourechi V, Lankarani M, Schryver PG, Vanness DJ, Long KH, and Klee GG
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OBJECTIVE: To determine factors that influence clinicians' decisions to treat subclinical hypothyroidism. PATIENTS AND METHODS: We studied patients living within 120 miles of our institution in Rochester, Minn, whose serum thyrotropin value was between 5.1 and 10.0 mIU/L from January 1, 1995, through December 31,1996. Exclusion criteria were history of thyroid disease or prior abnormal thyrotropin level and fewer than 5 follow-up visits or fewer than 2 follow-up thyrotropin measurements. Of the 2655 patients in this cohort, only 55% (1466) had measurement of thyroid microsomal antibodies (TMAb). From this group, records of 539 patients were selected randomly according to antibody status (238 with positive, 199 with negative, and 102 with no TMAb measurement). After exclusion of patients receiving thyroxine replacement and other medications affecting thyroid function, patients with postpartum thyroiditis, and patients in the intensive care unit, data from 450 patients were analyzed. RESULTS: Thyroxine therapy was prescribed for 39% of the patients with thyrotropin levels between 5.1 and 10.0 mIU/L. In multivariate analysis, TMAb status (P < .001), index thyrotropin (P < .002), and free thyroxine (FT4) (P = .03) were the strongest predictors for the decision to treat. Fifty-nine percent of the patients with positive TMAb were treated compared with 24% of those with negative TMAb and 30% of those who did not have a TMAb test. The mean thyrotropin level in the treated group was 7.1 mIU/L compared with 63 mIU/L in the untreated group. The mean FT4 level was 1.08 ng/dL in the treated group who had this measured compared with 1.16 ng/dL in the untreated group. Treated patients were younger than untreated patients (56.5 years vs 60.6 years), and the proportion of female patients was higher in the treated group compared with the untreated group (75.8% vs 65.2%); however, neither of these differences was significant after correction for the multiple comparisons. In multivariate analysis neither age nor sex was a significant predictor of treatment, but in the subgroup comparison, patients aged 31 to 50 years were twice as likely to be treated compared with those aged 61 to 80 years. CONCLUSION: Among patients with serum thyrotropin levels of 5.1 to 10.0 mIU/L, those with positive TMAb values, those with higher thyrotropin values, and those with lower FT4 values were more likely to receive thyroxine therapy. Younger patients were more likely to be treated than older patients. [ABSTRACT FROM AUTHOR]
- Published
- 2003
22. Prospective validation of microseminoprotein-β added to the 4Kscore in predicting high-grade prostate cancer in an international multicentre cohort.
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Lonergan PE, Vertosick EA, Assel M, Sjoberg DD, Haese A, Graefen M, Boorjian SA, Klee GG, Cooperberg MR, Pettersson K, Routila E, Vickers AJ, and Lilja H
- Subjects
- Aged, Cohort Studies, Humans, Internationality, Male, Middle Aged, Neoplasm Grading, Prospective Studies, Biomarkers, Tumor blood, Kallikreins blood, Models, Statistical, Prostatic Neoplasms blood, Prostatic Neoplasms pathology, Prostatic Secretory Proteins blood
- Abstract
Objectives: To prospectively evaluate the performance of a pre-specified statistical model based on four kallikrein markers in blood (total prostate-specific antigen [PSA], free PSA, intact PSA, and human kallikrein-related peptidase 2), commercially available as the 4Kscore, in predicting Gleason Grade Group (GG) ≥2 prostate cancer at biopsy in an international multicentre study at three academic medical centres, and whether microseminoprotein-β (MSP) adds predictive value., Patients and Methods: A total of 984 men were prospectively enrolled at three academic centres. The primary outcome was GG ≥2 on prostate biopsy. Three pre-specified statistical models were used: a base model including PSA, age, digital rectal examination and prior negative biopsy; a model that added free PSA to the base model; and the 4Kscore., Results: A total of 947 men were included in the final analysis and 273 (29%) had GG ≥2 on prostate biopsy. The base model area under the receiver operating characteristic curve of 0.775 increased to 0.802 with the addition of free PSA, and to 0.824 for the 4Kscore. Adding MSP to the 4Kscore model yielded an increase (0.014-0.019) in discrimination. In decision-curve analysis of clinical utility, the 4Kscore showed a benefit starting at a 7.5% threshold., Conclusion: A prospective multicentre evaluation of a pre-specified model based on four kallikrein markers (4Kscore) with the addition of MSP improves the predictive discrimination for GG ≥2 prostate cancer on biopsy and could be used to inform biopsy decision-making., (© 2020 The Authors BJU International © 2020 BJU International Published by John Wiley & Sons Ltd.)
- Published
- 2021
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23. Kallikrein markers performance in pretreatment blood to predict early prostate cancer recurrence and metastasis after radical prostatectomy among very high-risk men.
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Assel MJ, Ulmert HD, Karnes RJ, Boorjian SA, Hillman DW, Vickers AJ, Klee GG, and Lilja H
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- Aged, Biomarkers, Tumor blood, Humans, Male, Middle Aged, Neoplasm Grading, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasm Recurrence, Local pathology, Prostate-Specific Antigen blood, Prostatectomy, Prostatic Neoplasms pathology, Prostatic Neoplasms surgery, Risk Factors, Seminal Vesicles pathology, Kallikreins blood, Neoplasm Recurrence, Local blood, Prostatic Neoplasms blood
- Abstract
Background: To assess whether a prespecified statistical model based on the four kallikrein markers measured in blood-total, free, and intact prostate-specific antigen (PSA), together with human kallikrein-related peptidase 2 (hK2)-or any individual marker measured in pretreatment serum were associated with biochemical recurrence-free (BCR) or metastasis-free survival after radical prostatectomy (RP) in a subgroup of men with very high-risk disease., Methods: We identified 106 men treated at Mayo Clinic from 2004 to 2008 with pathological Gleason grade group 4 to 5 or seminal vesicle invasion at RP. Univariable and multivariable Cox models were used to test the association between standard predictors (Kattan nomogram and GPSM [Gleason, PSA, seminal vesicle and margin status] score), kallikrein panel, and individual kallikrein markers with the outcomes., Results: BCR and metastasis occurred in 67 and 30 patients, respectively. The median follow-up for patients who did not develop a BCR was 10.3 years (interquartile range = 8.2-11.8). In this high-risk group, neither Kattan risk, GPSM score, or the kallikrein panel model was associated with either outcome. However, after adjusting for Kattan risk and GPSM score, separately, preoperative intact PSA was associated with both outcomes while hK2 was associated with metastasis-free survival., Conclusions: Conventional risk prediction tools were poor discriminators for risk of adverse outcomes after RP (Kattan risk and GPSM risk) in patients with very high-risk disease. Further studies are needed to define the role of individual kallikrein marker forms in the blood to predict adverse prostate cancer outcomes after RP in this high-risk setting., (© 2019 Wiley Periodicals, Inc.)
- Published
- 2020
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24. Reference Intervals: Comparison of Calculation Methods and Evaluation of Procedures for Merging Reference Measurements From Two US Medical Centers.
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Klee GG, Ichihara K, Ozarda Y, Baumann NA, Straseski J, Bryant SC, and Wood-Wentz CM
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- Humans, Reference Values, Clinical Laboratory Techniques standards
- Abstract
Objectives: To analyze consistency of reference limits and widths of reference intervals (RIs) calculated by six procedures and evaluate a protocol for merging intrainstitutional reference data., Methods: The differences between reference limits were compared with "optimal" bias goals. Also, widths of the RIs were compared. RIs were calculated using Mayo-SAS quantile, EP Evaluator, and four International Federation of Clinical Chemistry and Laboratory Medicine methods: parametric and nonparametric (NP) with and without latent abnormal values exclusion (LAVE). Regression parameters from cotested samples were evaluated for harmonizing intrainstitutional reference data., Results: Mayo-SAS quintile, LAVE(-)NP, and EP Evaluator generated similar RIs, but these RIs often were wider than RIs from parametric procedures. LAVE procedures generated narrower RIs for nutritional and inflammatory markers. Transformation with regression parameters did not ensure homogeneity of merged data., Conclusions: Parametric methods are recommended when inappropriate values cannot be excluded. The nonparametric procedures may generate wider RIs. Data sets larger than 200 are recommended for robust estimates. Caution should be exercised when merging intrainstitutional data.
- Published
- 2018
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25. Criteria for assigning laboratory measurands to models for analytical performance specifications defined in the 1st EFLM Strategic Conference.
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Ceriotti F, Fernandez-Calle P, Klee GG, Nordin G, Sandberg S, Streichert T, Vives-Corrons JL, and Panteghini M
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- Cholesterol blood, Creatinine blood, Cystatin C blood, Electrolytes blood, Glucose analysis, Glycated Hemoglobin analysis, Humans, Minerals blood, Serum Albumin analysis, Troponin blood, Uric Acid blood, Blood Chemical Analysis, Clinical Laboratory Techniques methods, Clinical Laboratory Techniques standards
- Abstract
This paper, prepared by the EFLM Task and Finish Group on Allocation of laboratory tests to different models for performance specifications (TFG-DM), is dealing with criteria for allocating measurands to the different models for analytical performance specifications (APS) recognized in the 1st EFLM Strategic Conference Consensus Statement. Model 1, based on the effect of APS on clinical outcome, is the model of choice for measurands that have a central role in the decision-making of a specific disease or clinical situation and where cut-off/decision limits are established for either diagnosing, screening or monitoring. Total cholesterol, glucose, HbA1c, serum albumin and cardiac troponins represent practical examples. Model 2 is based on components of biological variation and should be applied to measurands that do not have a central role in a specific disease or clinical situation, but where the concentration of the measurand is in a steady state. This is best achieved for measurands under strict homeostatic control in order to preserve their concentrations in the body fluid of interest, but it can also be applied to other measurands that are in a steady state in biological fluids. In this case, it is expected that the "noise" produced by the measurement procedure will not significantly alter the signal provided by the concentration of the measurand. This model especially applies to electrolytes and minerals in blood plasma (sodium, potassium, chloride, bicarbonate, calcium, magnesium, inorganic phosphate) and to creatinine, cystatin C, uric acid and total protein in plasma. Model 3, based on state-of-the-art of the measurement, should be used for all the measurands that cannot be included in models 1 or 2.
- Published
- 2017
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26. Interleukins 6 and 8 and abdominal fat depots are distinct correlates of lipid moieties in healthy pre- and postmenopausal women.
- Author
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Veldhuis JD, Dyer RB, Trushin SA, Bondar OP, Singh RJ, and Klee GG
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- Abdominal Fat diagnostic imaging, Adult, Aged, Female, Gonadal Steroid Hormones blood, Humans, Interleukin-6 blood, Interleukin-8 blood, Middle Aged, Sex Hormone-Binding Globulin metabolism, Tomography, X-Ray Computed, Young Adult, Abdominal Fat metabolism, Lipids blood, Postmenopause blood, Premenopause blood
- Abstract
Available data associate lipids concentrations in men with body mass index, anabolic steroids, age, and certain cytokines. Data were less clear in women, especially across the full adult lifespan, and when segmented by premenopausal and postmenopausal status., Subjects: 120 healthy women (60 premenopausal and 60 postmenopausal) in Olmsted County, MN, USA, a stable well studied clinical population. Dependent variables: measurements of 10 h fasting high-density lipoprotein cholesterol, total cholesterol, low-density lipoprotein cholesterol, and triglycerides., Independent Variables: testosterone, estrone, estradiol, 5-alpha-dihydrotestosterone, and sex-hormone binding globulin (by mass spectrometry); insulin, glucose, and albumin; abdominal visceral, subcutaneous, and total abdominal fat [abdominal visceral fat, subcutaneous fat, total abdominal fat by computerized tomography scan]; and a panel of cytokines (by enzyme-linked immunosorbent assay). Multivariate forward-selection linear-regression analysis was applied constrained to P < 0.01. Lifetime data: High-density lipoprotein cholesterol was correlated jointly with age (P < 0.0001, positively), abdominal visceral fat (P < 0.0001, negatively), and interleukin-6 (0.0063, negatively), together explaining 28.1 % of its variance (P = 2.3 × 10
-8 ). Total cholesterol was associated positively with multivariate age only (P = 6.9 × 10-4 , 9.3 % of variance). Triglycerides correlated weakly with sex-hormone binding globulin (P = 0.0115), and strongly with abdominal visceral fat (P < 0.0001), and interleukin-6 (P = 0.0016) all positively (P = 1.6 × 10-12 , 38.9 % of variance). Non high-density lipoprotein cholesterol and low-density lipoprotein cholesterol correlated positively with both total abdominal fat and interleukin-8 (P = 2.0 × 10-5 , 16.9 % of variance; and P = 0.0031, 9.4 % of variance, respectively). Premenopausal vs. postmenopausal comparisons identified specific relationships that were stronger in premenopausal than postmenopausal individuals, and vice versa. Age was a stronger correlate of low-density lipoprotein cholesterol; interleukin-6 of triglycerides and high-density lipoprotein; and both sex-hormone binding globulin and total abdominal fat of non high-density lipoprotein cholesterol in premenopausal than postmenopausal women. Conversely, sex-hormone binding globulin, abdominal visceral fat, interleukin-8, adiponectin were stronger correlates of triglycerides; abdominal visceral fat, and testosterone of high-density lipoprotein cholesterol; and age of both non high-density lipoprotein and low-density lipoprotein in postmenopausal than premenopausal women. Our data delineate correlations of total abdominal fat and interleukin-8 (both positively) with non high-density lipoprotein cholesterol and low-density lipoprotein cholesterol in healthy women across the full age range of 21-79 years along with even more specific associations in premenopausal and postmenopausal individuals. Whether some of these outcomes reflect causal relationships would require longitudinal and interventional or genetic studies., Competing Interests: The authors declare they have no conflict of interest.- Published
- 2016
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27. Multiple calibrator measurements improve accuracy and stability estimates of automated assays.
- Author
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Akbas N, Budd JR, and Klee GG
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- Calibration, Immunoassay instrumentation, Immunoassay standards, Quality Improvement, Reproducibility of Results, Luteinizing Hormone analysis, Triiodothyronine analysis, Vitamin B 12 analysis
- Abstract
Objectives: The effects of combining multiple calibrations on assay accuracy (bias) and measurement of calibration stability were investigated for total triiodothyronine (TT3), vitamin B12 and luteinizing hormone (LH) using Beckman Coulter's Access 2 analyzer., Methods: Three calibration procedures (CC1, CC2 and CC3) combined 12, 34 and 56 calibrator measurements over 1, 2, and 3 days. Bias was calculated between target values and average measured value over 3 consecutive days after calibration. Using regression analysis of calibrator measurements versus measurement date, calibration stability was determined as the maximum number of days before a calibrator measurement exceeded 5% tolerance limits., Results: Competitive assays (TT3, vitamin B12) had positive time regression slopes, while sandwich assay (LH) had a negative slope. Bias values for TT3 were -2.49%, 1.49%, and -0.50% using CC1, CC2 and CC3 respectively, with calibrator stability of 32, 20, and 30 days. Bias values for vitamin B12 were 2.44%, 0.91%, and -0.50%, with calibrator stability of 4, 9, and 12 days. Bias values for LH were 2.26%, 1.44% and -0.29% with calibrator stability of >43, 39 and 36 days. Measured stability was more consistent across calibration procedures using percent change rather than difference from target: 26 days for TT3, 12 days for B12 and 31 days for LH., Conclusions: Averaging over multiple calibrations produced smaller bias, consistent with improved accuracy. Time regression slopes in percent change were unaffected by number of calibration measurements but calibrator stability measured from the target value was highly affected by the calibrator value at time zero.
- Published
- 2016
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28. Androgen Receptor Upregulation Mediates Radioresistance after Ionizing Radiation.
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Spratt DE, Evans MJ, Davis BJ, Doran MG, Lee MX, Shah N, Wongvipat J, Carnazza KE, Klee GG, Polkinghorn W, Tindall DJ, Lewis JS, and Sawyers CL
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- Animals, Blotting, Western, Cell Line, Tumor, Comet Assay, Fluorescent Antibody Technique, Humans, Luminescent Measurements, Male, Mice, Mice, SCID, Prostatic Neoplasms metabolism, Real-Time Polymerase Chain Reaction, Up-Regulation, Xenograft Model Antitumor Assays, Prostatic Neoplasms radiotherapy, Radiation Tolerance physiology, Receptors, Androgen biosynthesis
- Abstract
Clinical trials have established the benefit of androgen deprivation therapy (ADT) combined with radiotherapy in prostate cancer. ADT sensitizes prostate cancer to radiotherapy-induced death at least in part through inhibition of DNA repair machinery, but for unknown reasons, adjuvant ADT provides further survival benefits. Here, we show that androgen receptor (AR) expression and activity are durably upregulated following radiotherapy in multiple human prostate cancer models in vitro and in vivo. Moreover, the degree of AR upregulation correlates with survival in vitro and time to tumor progression in animal models. We also provide evidence of AR pathway upregulation, measured by a rise in serum levels of AR-regulated hK2 protein, in nearly 20% of patients after radiotherapy. Furthermore, these men were three-fold more likely to experience subsequent biochemical failure. Collectively, these data demonstrate that radiotherapy can upregulate AR signaling after therapy to an extent that negatively affects disease progression and/or survival., (©2015 American Association for Cancer Research.)
- Published
- 2015
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29. The prostate health index selectively identifies clinically significant prostate cancer.
- Author
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Loeb S, Sanda MG, Broyles DL, Shin SS, Bangma CH, Wei JT, Partin AW, Klee GG, Slawin KM, Marks LS, van Schaik RH, Chan DW, Sokoll LJ, Cruz AB, Mizrahi IA, and Catalona WJ
- Subjects
- Aged, Aged, 80 and over, Health Status Indicators, Humans, Male, Middle Aged, Prospective Studies, Prostate-Specific Antigen blood, Prostatic Neoplasms blood, Prostatic Neoplasms diagnosis, Protein Precursors blood
- Abstract
Purpose: The Prostate Health Index (phi) is a new test combining total, free and [-2]proPSA into a single score. It was recently approved by the FDA and is now commercially available in the U.S., Europe and Australia. We investigate whether phi improves specificity for detecting clinically significant prostate cancer and can help reduce prostate cancer over diagnosis., Materials and Methods: From a multicenter prospective trial we identified 658 men age 50 years or older with prostate specific antigen 4 to 10 ng/ml and normal digital rectal examination who underwent prostate biopsy. In this population we compared the performance of prostate specific antigen, % free prostate specific antigen, [-2]proPSA and phi to predict biopsy results and, specifically, the presence of clinically significant prostate cancer using multiple criteria., Results: The Prostate Health Index was significantly higher in men with Gleason 7 or greater and "Epstein significant" cancer. On receiver operating characteristic analysis phi had the highest AUC for overall prostate cancer (AUCs phi 0.708, percent free prostate specific antigen 0.648, [-2]proPSA 0.550 and prostate specific antigen 0.516), Gleason 7 or greater (AUCs phi 0.707, percent free prostate specific antigen 0.661, [-2]proPSA 0.558, prostate specific antigen 0.551) and significant prostate cancer (AUCs phi 0.698, percent free prostate specific antigen 0.654, [-2]proPSA 0.550, prostate specific antigen 0.549). At the 90% sensitivity cut point for phi (a score less than 28.6) 30.1% of patients could have been spared an unnecessary biopsy for benign disease or insignificant prostate cancer compared to 21.7% using percent free prostate specific antigen., Conclusions: The new phi test outperforms its individual components of total, free and [-2]proPSA for the identification of clinically significant prostate cancer. Phi may be useful as part of a multivariable approach to reduce prostate biopsies and over diagnosis., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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30. The cistrome and gene signature of androgen receptor splice variants in castration resistant prostate cancer cells.
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Lu J, Lonergan PE, Nacusi LP, Wang L, Schmidt LJ, Sun Z, Van der Steen T, Boorjian SA, Kosari F, Vasmatzis G, Klee GG, Balk SP, Huang H, Wang C, and Tindall DJ
- Subjects
- High-Throughput Nucleotide Sequencing, Humans, Male, Protein Isoforms, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic, Prostatic Neoplasms, Castration-Resistant genetics, Receptors, Androgen genetics, Transcriptome
- Abstract
Purpose: Spliced variant forms of androgen receptor were recently identified in castration resistant prostate cancer cell lines and clinical samples. We identified the cistrome and gene signature of androgen receptor splice variants in castration resistant prostate cancer cell lines and determined the clinical significance of androgen receptor splice variant regulated genes., Materials and Methods: The castration resistant prostate cancer cell line 22Rv1, which expresses full-length androgen receptor and androgen receptor splice variants endogenously, was used as the research model. We established 22Rv1-ARFL(-)/ARV(+) and 22Rv1-ARFL(-)/ARV(-) through RNA interference. Chromatin immunoprecipitation coupled with next generation sequencing and microarray techniques were used to identify the cistrome and gene expression profiles of androgen receptor splice variants in the absence of androgen., Results: Androgen receptor splice variant binding sites were identified in 22Rv1-ARFL(-)/ARV(+). A gene set was regulated uniquely by androgen receptor splice variants but not by full-length androgen receptor in the absence of androgen. Integrated analysis revealed that some genes were directly modulated by androgen receptor splice variants. Unsupervised clustering analysis showed that the androgen receptor splice variant gene signature differentiated benign from malignant prostate tissue as well as localized prostate cancer from metastatic castration resistant prostate cancer specimens. Some genes that were modulated uniquely by androgen receptor splice variants also correlated with histological grade and biochemical failure., Conclusions: Androgen receptor splice variants can bind to DNA independent of full-length androgen receptor in the absence of androgen and modulate a unique set of genes that is not regulated by full-length androgen receptor. The androgen receptor splice variant gene signature correlates with disease progression. It distinguishes primary cancer from castration resistant prostate cancer specimens and benign from malignant prostate specimens., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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31. Evaluation of Beckman Coulter DxI 800 immunoassay system using clinically oriented performance goals.
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Akbas N, Schryver PG, Algeciras-Schimnich A, Baumann NA, Block DR, Budd JR, Gaston SJ, and Klee GG
- Subjects
- Ferritins analysis, Reproducibility of Results, Thyroxine analysis, Triiodothyronine analysis, Immunoassay methods
- Abstract
Objectives: We evaluated the analytical performance of 24 immunoassays using the Beckman Coulter DxI 800 immunoassay systems at Mayo Clinic, Rochester, MN for trueness, precision, detection limits, linearity, and consistency (across instruments and reagent lots)., Methods: Clinically oriented performance goals were defined using the following methods: trueness-published desirable accuracy limits, precision-published desirable biologic variation; detection limits - 0.1 percentile of patient test values, linearity - 50% of total error, and consistency-percentage test values crossing key decision points. Local data were collected for precision, linearity, and consistency. Data were provided by Beckman Coulter, Inc. for trueness and detection limits., Results: All evaluated assays except total thyroxine were within the proposed goals for trueness. Most of the assays met the proposed goals for precision (86% of intra-assay results and 75% of inter-assay results). Five assays had more than 15% of the test results below the minimum detection limits. Carcinoembryonic antigen, total thyroxine and free triiodothyronine exceeded the proposed goals of ±6.3%, ±5% and ±5.7% for dilution linearity. All evaluated assays were within the proposed goals for instrument consistency. Lot-to-lot consistency results for cortisol, ferritin and total thyroxine exceeded the proposed goals of 3.3%, 11.4% and 7% at one medical decision level, while vitamin B12 exceeded the proposed goals of 5.2% and 3.8% at two decision levels., Conclusions: The Beckman Coulter DxI 800 immunoassay system meets most of these proposed goals, even though these clinically focused performance goals represent relatively stringent limits., (Copyright © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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32. Serum concentrations of prostate-specific antigen measured using immune extraction, trypsin digestion, and tandem mass spectrometry quantification of LSEPAELTDAVK peptide.
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Klee EW, Bondar OP, Goodmanson MK, Trushin SA, Bergstralh EJ, Singh RJ, Anderson NL, and Klee GG
- Subjects
- Analytic Sample Preparation Methods, Antibodies, Monoclonal chemistry, Calibration, Humans, Indicators and Reagents chemistry, Male, Peptide Fragments chemistry, Peptide Fragments isolation & purification, Peptide Fragments metabolism, Prostate-Specific Antigen chemistry, Prostate-Specific Antigen isolation & purification, Prostate-Specific Antigen metabolism, Prostatic Neoplasms diagnosis, Proteolysis, ROC Curve, Reproducibility of Results, Tandem Mass Spectrometry, Trypsin metabolism, Peptide Fragments analysis, Prostate-Specific Antigen blood, Prostatic Neoplasms blood
- Abstract
Context: Prostate-specific antigen (PSA) is a 34-kDa glycoprotein with chymotrypsin-like enzyme activity that circulates both in free forms and complexed to various enzyme inhibitors including antichymotrypsin and α2-macroglobulin. Prostate-specific antigen bound to α2-macroglobulin is not detected by commercial PSA immunoassays., Objective: To develop a mass spectrometry assay that detects the same forms of PSA as the immunoassays, which could serve as a reference for harmonizing PSA immunoassays., Design: Prostate-specific antigen was immune extracted from serum, trypsin was digested, and the LSEPAELTDAVK peptide was quantitated on an API 5000 spectrometer. Calibrators were made by adding 10% free and 90% antichymotrypsin-bound PSA to female sera. The assay was standardized to the World Health Organization 96/670 reference standard. Validation of clinical utility and comparisons with 2 immunoassays (Roche cobas and Beckman Access) were performed using frozen sera aliquots from 100 men undergoing prostate biopsy (50 negative, 50 with cancer) and 5 serial samples collected over time from 5 men with advanced prostate cancer., Results: The antibody extraction efficiency was greater than 99%. The assay has an analytic range from 1.2 to 76 ng/mL, with precision ranging from 8.6% at 1.5 ng/mL to 5.4% at 27 ng/mL. The mass spectrometry assay correlated well with 2 immunoassays. All 3 assays showed statistically equivalent separation of prostate cancer from benign disease using receiver operating characteristic curve analysis., Conclusions: This mass spectrometry assay can reliably measure PSA concentrations in human serum and could serve as a reference standard for harmonizing PSA immunoassays.
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- 2014
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33. Verifying performance characteristics of quantitative analytical systems: calibration verification, linearity, and analytical measurement range.
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Killeen AA, Long T, Souers R, Styer P, Ventura CB, and Klee GG
- Subjects
- Calibration standards, Chemistry Techniques, Analytical standards, Drug Monitoring standards, Humans, Linear Models, Reference Values, Evaluation Studies as Topic, Laboratories standards, Pathology, Clinical standards, Systems Analysis
- Abstract
Context: Both the regulations in the Clinical Laboratory Improvement Amendments of 1988 (CLIA) and the checklists of the College of American Pathologists (CAP) Laboratory Accreditation Program require clinical laboratories to verify performance characteristics of quantitative test systems. Laboratories must verify performance claims when introducing an unmodified, US Food and Drug Administration-cleared or approved test system, and they must comply with requirements for periodic calibration and calibration verification for existing test systems. They must also periodically verify the analytical measurement range of many quantitative test systems., Objective: To provide definitions for many of the terms used in these regulations, to describe a set of basic analyses that laboratories may adapt to demonstrate compliance with both CLIA and the CAP Laboratory Accreditation Program checklists for performing calibration verification and for verifying the analytical measurement range of test systems, to review some of the recommended procedures for establishing performance goals, and to provide data illustrating the performance goals used in some of the CAP's calibration verification and linearity surveys., Data Sources: The CAP's calibration verification and linearity survey programs, the CLIA regulations, the Laboratory Accreditation Program requirements, and published literature were used to meet these objectives., Conclusions: Calibration verification and linearity and analytical measurement range verification should be performed using suitable materials with assessment of results using well-defined evaluation protocols. We describe the CAP's calibration verification and linearity programs that may be used for these purposes.
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- 2014
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34. Immunologic and mass-spectrometric estimates of SHBG concentrations in healthy women.
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Veldhuis JD, Dyer RB, Trushin SA, Bondar OP, Singh RJ, and Klee GG
- Subjects
- Adult, Aged, Blood Glucose metabolism, Body Mass Index, Cholesterol, HDL blood, Estradiol blood, Estrone blood, Female, Humans, Insulin blood, Interleukins blood, Menopause, Middle Aged, Serum Albumin metabolism, Triglycerides blood, Tumor Necrosis Factor-alpha blood, Intra-Abdominal Fat metabolism, Mass Spectrometry, Sex Hormone-Binding Globulin metabolism, Testosterone blood
- Abstract
Objective: Sex-hormone binding globulin (SHBG) concentrations across the adult female lifespan are not well defined. To address this knowledge gap, SHBG was quantified by both immunological and criterion methods, viz, mass spectrometry (MS)., Setting: Center for Translational Science Activities (CTSA)., Participants: Healthy nonpregnant women (N=120) ages 21 to 79 years., Outcomes: SHBG, testosterone (T), estradiol (E2) and estrone (E1) each determined by MS. Uni- and multivariate regression of SHBG concentrations on age, body mass index (BMI), total and visceral abdominal fat (TAF, AVF), albumin, glucose, insulin, sex steroids, selected cytokines, blood pressure, and lipids., Results: By univariate regression, MS-estimated SHBG correlated negatively with BMI, TAF, AVF, insulin, free T and bioavailable T (bio T) (each P≤10(-4)), but not with blood pressure or lipids. By stepwise multivariate regression analysis, free and total T (both positive) and bio T (negative) were correlated with SHBG in all 4 assays (each P<10(-15), R(2)≥0.481). In addition, TAF and BMI were negatively associated with SHBG (P≤0.0066) in 2 SHBG assays, and estrone and IL-8 with SHBG weakly (P≤0.035) in one SHBG assay each. When nonsignificant cytokines were excluded, SHBG was jointly associated with AVF, total T and HDL (P<10(-9), R(2)=0.358)., Conclusion: According to MS, three metabolic factors, T, AVF and HDL, together explain more than one-third of the interindividual variation in SHBG levels. We speculate that these measures reflect insulin action., (Copyright © 2014 Elsevier Inc. All rights reserved.)
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- 2014
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35. Reprint of "Influence of analytical bias and imprecision on the number of false positive results using Guideline-Driven Medical Decision Limits".
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Hyltoft Petersen P and Klee GG
- Subjects
- Bias, Clinical Laboratory Techniques standards, False Positive Reactions, Humans, Limit of Detection, Probability, Quality Assurance, Health Care, Reference Values, Reproducibility of Results, Research Design, Clinical Laboratory Techniques methods, Practice Guidelines as Topic
- Abstract
Background: Diagnostic decisions based on decision limits according to medical guidelines are different from the majority of clinical decisions due to the strict dichotomization of patients into diseased and non-diseased. Consequently, the influence of analytical performance is more critical than for other diagnostic decisions where much other information is included. The aim of this opinion paper is to investigate consequences of analytical quality and other circumstances for the outcome of "Guideline-Driven Medical Decision Limits"., Terms: Effects of analytical bias and imprecision should be investigated separately and analytical quality specifications should be estimated accordingly., Biological Variation and Analytical Performance: Use of sharp decision limits doesn't consider biological variation and effects of this variation are closely connected with the effects of analytical performance. Such relationships are investigated for the guidelines for HbA1c in diagnosis of diabetes and in risk of coronary heart disease based on serum cholesterol. The effects of a second sampling in diagnosis give dramatic reduction in the effects of analytical quality showing minimal influence of imprecision up to 3 to 5% for two independent samplings, whereas the reduction in bias is more moderate and a 2% increase in concentration doubles the percentage of false positive diagnoses, both for HbA1c and cholesterol., Frequency of Follow-Up Laboratory Tests: An alternative approach comes from the current application of guidelines for follow-up laboratory tests according to clinical procedure orders, e.g. frequency of parathyroid hormone requests as a function of serum calcium concentrations. Here, the specifications for bias can be evaluated from the functional increase in requests for increasing serum calcium concentrations., Probability Function for Diagnoses: In consequence of the difficulties with biological variation and the practical utilization of concentration dependence of frequency of follow-up laboratory tests already in use, a kind of probability function for diagnosis as function of the key-analyte is proposed., (Copyright © 2014. Published by Elsevier B.V.)
- Published
- 2014
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36. Mass spectrometry measurements of prostate-specific antigen (PSA) peptides derived from immune-extracted PSA provide a potential strategy for harmonizing immunoassay differences.
- Author
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Klee EW, Bondar OP, Goodmanson MK, Trushin SA, Singh RJ, Anderson NL, and Klee GG
- Subjects
- Amino Acid Sequence, Chromatography, Liquid methods, Epitopes, Female, Humans, Immunoassay standards, Male, Prostate-Specific Antigen immunology, Prostate-Specific Antigen metabolism, Reproducibility of Results, Trypsin metabolism, Peptide Fragments blood, Prostate-Specific Antigen chemistry, Tandem Mass Spectrometry methods
- Abstract
Objectives: Harmonization of prostate-specific antigen (PSA) immunoassays is important for good patient care. The specificity of the antibodies used to detect circulating PSA could cause differences in the PSA measurements., Methods: We used mass spectrometry (MS) to quantitate the concentration of five peptides cleaved from trypsin digestion of PSA and compared these measurements with six automated immunoassays. Linear regression and a mixed-effects model were used to analyze the results., Results: PSA measurements from the immunoassays and the five MS peptide assays were highly correlated (R(2) > 0.99), but the recovery of the World Health Organization standard and the regression slopes differed across assays. The same relative patterns of immunoassay differences were seen in comparing their results with each of the five MS peptide measurements from different parts of the circulating PSA molecules., Conclusions: Mass spectrometry quantitation of peptides derived from trypsin digestion of immune-extracted PSA could be used to harmonize PSA immunoassays.
- Published
- 2014
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37. Influence of analytical bias and imprecision on the number of false positive results using Guideline-Driven Medical Decision Limits.
- Author
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Hyltoft Petersen P and Klee GG
- Subjects
- Bias, Calcium blood, Coronary Disease blood, Coronary Disease diagnosis, Diabetes Mellitus diagnosis, False Positive Reactions, Humans, Cholesterol blood, Clinical Laboratory Techniques standards, Decision Making, Computer-Assisted, Glycated Hemoglobin analysis, Practice Guidelines as Topic
- Abstract
Background: Diagnostic decisions based on decision limits according to medical guidelines are different from the majority of clinical decisions due to the strict dichotomization of patients into diseased and non-diseased. Consequently, the influence of analytical performance is more critical than for other diagnostic decisions where much other information is included. The aim of this opinion paper is to investigate consequences of analytical quality and other circumstances for the outcome of "Guideline-Driven Medical Decision Limits"., Terms: Effects of analytical bias and imprecision should be investigated separately and analytical quality specifications should be estimated accordingly., Biological Variation and Analytical Performance: Use of sharp decision limits doesn't consider biological variation and effects of this variation are closely connected with the effects of analytical performance. Such relationships are investigated for the guidelines for HbA1c in diagnosis of diabetes and in risk of coronary heart disease based on serum cholesterol. The effects of a second sampling in diagnosis give dramatic reduction in the effects of analytical quality showing minimal influence of imprecision up to 3 to 5% for two independent samplings, whereas the reduction in bias is more moderate and a 2% increase in concentration doubles the percentage of false positive diagnoses, both for HbA1c and cholesterol., Frequency of Follow-Up Laboratory Tests: An alternative approach comes from the current application of guidelines for follow-up laboratory tests according to clinical procedure orders, e.g. frequency of parathyroid hormone requests as a function of serum calcium concentrations. Here, the specifications for bias can be evaluated from the functional increase in requests for increasing serum calcium concentrations., Probability Function for Diagnoses: In consequence of the difficulties with biological variation and the practical utilization of concentration dependence of frequency of follow-up laboratory tests already in use, a kind of probability function for diagnosis as function of the key-analyte is proposed., (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
38. Immunological and mass spectrometric assays of SHBG: consistent and inconsistent metabolic associations in healthy men.
- Author
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Veldhuis JD, Bondar OP, Dyer RB, Trushin SA, Klee EW, Singh RJ, and Klee GG
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Health, Humans, Immunoassay methods, Male, Mass Spectrometry methods, Metabolic Diseases epidemiology, Metabolic Diseases etiology, Middle Aged, Sex Factors, Young Adult, Metabolic Diseases blood, Sex Hormone-Binding Globulin analysis, Sex Hormone-Binding Globulin metabolism
- Abstract
Context: SHBG concentrations correlate inconsistently with metabolic parameters., Hypothesis: SHBG assay platforms contribute to nonuniformities according to the literature., Design: The design of the study was a noninterventional quantification of SHBG by two immuno- and two mass spectrometric assays and abdominal visceral fat by computed tomography scan., Setting: The study was conducted at the Center for Translational Science Activities., Participants: Healthy men (n=120) aged 18-80 years with a body mass index of 20-43 kg/m2 participated I the study., Outcomes: Outcomes of the study included a correlation of log SHBG with age, metabolic surrogates [body mass index, albumin, glucose, insulin, abdominal (total and visceral) fat, homeostasis model assessment insulin resistance index], sex steroids (estrone, 17β-estradiol, T, and dihydrotestosterone by mass spectrometry), and adipocytokines (IL-1β, IL-6, IL-8, IL-10 and IL-12, TNF-α, and adiponectin)., Results: By univariate regression, age (P<10(-4)), dihydrotestosterone (P<10(-4)), T (P≤.00022), and adiponectin (P≤.0084) were positive correlates, and insulin and homeostasis model assessment insulin resistance index were negative correlates (P≤.0060) of SHBG in all four assays. Stepwise multivariate analysis unveiled that age and T together could explain 38.1%-52.5% of the statistical variance in SHBG in all assays (P<10(-11)). Multivariate regression without sex steroids unveiled that age (P<10(-5)) and insulin (P<10(-3)) are jointly associated with SHBG levels in the four assays with overall R2=0.215-0.293 and P<10(-6). In one immunological SHBG assay each, abdominal visceral fat and adiponectin were weak multivariates also., Conclusion: Immunological and mass spectrometric SHBG assays yield both consistent and inconsistent correlations with key metabolic variables in healthy men, thereby potentially explaining earlier inconsistencies in the literature.
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- 2014
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39. Racial differences in longitudinal changes in serum prostate-specific antigen levels: the Olmsted County Study and the Flint Men's Health Study.
- Author
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Sarma AV, St Sauver JL, Jacobson DJ, McGree ME, Klee GG, Lieber MM, Girman CJ, Hollingsworth JM, and Jacobsen SJ
- Subjects
- Adult, Aged, Humans, Male, Men's Health, Middle Aged, Prospective Studies, Black or African American, Prostate-Specific Antigen blood, White People
- Abstract
Objective: To determine the distribution of, and racial differences in, changes in prostate-specific antigen (PSA) from a population-based sample of men., Materials and Methods: Data from 2 prospective cohort studies of a random sample of white men, aged 40-79 years in 1990, followed biennially through 2007, and African American men, aged 40-79 years in 1996, followed through 2000, were examined to assess the longitudinal changes in PSA concentrations. Serum PSA levels were determined at each examination for both cohorts and observations after a diagnosis of prostate cancer or treatment of benign prostatic hyperplasia were censored. The observed and estimated annual percentage of change in the serum PSA levels were examined by race., Results: At baseline, the median PSA level in the white men did not differ from the median level observed in the African American men (white men 0.9 ng/mL; African American men 0.9 ng/mL; P = .48). However, African American men had a much more rapid increase in the PSA level over time compared with the white men (median annual percent change in PSA for white men 3.6%/y, African American men 7.9%/y; P <.001)., Conclusion: These data suggest that African American men have more rapid rates of change in the PSA levels over time. If the difference in the rate of changes between African American and white men is an early indicator of future prostate cancer diagnosis, earlier detection in African American men could help to alleviate the racial disparities in prostate cancer diagnosis and mortality., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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40. Empiric validation of simulation models for estimating glucose meter performance criteria for moderate levels of glycemic control.
- Author
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Karon BS, Boyd JC, and Klee GG
- Subjects
- Blood Glucose metabolism, Dose-Response Relationship, Drug, Female, Glycated Hemoglobin metabolism, Humans, Male, Medication Errors, Blood Glucose drug effects, Computer Simulation, Glycated Hemoglobin drug effects, Hypoglycemic Agents administration & dosage, Insulin administration & dosage
- Abstract
Background: We used simulation modeling to relate glucose meter performance criteria to insulin dosing errors for patients on a moderate glycemic control protocol (glucose target, 110-150 mg/dL) and empirically validated assumptions from simulation models using observed glucose meter and laboratory glucose values obtained nearly simultaneously., Subjects and Methods: The 25,948 glucose values from 1,513 patients on a moderate glycemic control protocol were used to represent the expected distribution of glucose values in this patient population. Simulation models were used to relate glucose meter analytical performance to insulin dosing errors assuming 10%, 15%, or 20% total allowable error (TEa). In addition, 4,017 paired glucose meter and serum laboratory glucose measurements drawn within 5 min of each other were used to generate an empiric dataset to validate simulation model assumptions relating glucose meter performance to insulin dosing errors., Results: Large (three or more category) insulin dosing errors are predicted to occur only under the 20% TEa condition. Two category insulin dosing errors were common (6-20% of all insulin dosing decisions) when 20% TEa was assumed, but frequency decreased to only 0.2% of dosing decisions when 10% TEa was modeled. When insulin dosing error rates were measured empirically by comparing paired glucose meter and laboratory glucose values, insulin dosing error rates were very similar to those predicted for the 20% TEa condition., Conclusions: Both simulation models and empiric data demonstrate that glucose meters that perform at ≥20% TEa allow large insulin dosing errors during a moderate glycemic control protocol.
- Published
- 2013
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41. Validation of a genomic classifier that predicts metastasis following radical prostatectomy in an at risk patient population.
- Author
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Karnes RJ, Bergstralh EJ, Davicioni E, Ghadessi M, Buerki C, Mitra AP, Crisan A, Erho N, Vergara IA, Lam LL, Carlson R, Thompson DJ, Haddad Z, Zimmermann B, Sierocinski T, Triche TJ, Kollmeyer T, Ballman KV, Black PC, Klee GG, and Jenkins RB
- Subjects
- Cohort Studies, Humans, Male, Neoplasm Metastasis, Prognosis, Prostatic Neoplasms surgery, Genomics, Prostatectomy, Prostatic Neoplasms classification, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology
- Abstract
Purpose: Patients with locally advanced prostate cancer after radical prostatectomy are candidates for secondary therapy. However, this higher risk population is heterogeneous. Many cases do not metastasize even when conservatively managed. Given the limited specificity of pathological features to predict metastasis, newer risk prediction models are needed. We report a validation study of a genomic classifier that predicts metastasis after radical prostatectomy in a high risk population., Materials and Methods: A case-cohort design was used to sample 1,010 patients after radical prostatectomy at high risk for recurrence who were treated from 2000 to 2006. Patients had preoperative prostate specific antigen greater than 20 ng/ml, Gleason 8 or greater, pT3b or a Mayo Clinic nomogram score of 10 or greater. Patients with metastasis at diagnosis or any prior treatment for prostate cancer were excluded from analysis. A 20% random sampling created a subcohort that included all patients with metastasis. We generated 22-marker genomic classifier scores for 219 patients with available genomic data. ROC and decision curves, competing risk and weighted regression models were used to assess genomic classifier performance., Results: The genomic classifier AUC was 0.79 for predicting 5-year metastasis after radical prostatectomy. Decision curves showed that the genomic classifier net benefit exceeded that of clinical only models. The genomic classifier was the predominant predictor of metastasis on multivariable analysis. The cumulative incidence of metastasis 5 years after radical prostatectomy was 2.4%, 6.0% and 22.5% in patients with low (60%), intermediate (21%) and high (19%) genomic classifier scores, respectively (p<0.001)., Conclusions: Results indicate that genomic information from the primary tumor can identify patients with adverse pathological features who are most at risk for metastasis and potentially lethal prostate cancer., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
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42. Category-specific uncertainty modeling in clinical laboratory measurement processes.
- Author
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Ramamohan V, Yih Y, Abbott JT, and Klee GG
- Subjects
- Humans, Clinical Laboratory Techniques, Models, Statistical, Uncertainty
- Abstract
Background: A statement of measurement uncertainty describes the quality of a clinical assay analysis result, and uncertainty models of clinical assays can be used to evaluate and optimize laboratory protocols designed to minimize the measurement uncertainty associated with an assay. In this study, we propose a methodology to lend systematic structure to the uncertainty modeling process., Methods: Clinical laboratory assays are typically classified based on the chemical reaction involved, and therefore, based on the assay analysis methodology. We use this fact to demonstrate that uncertainty models for assays within the same category are structurally identical in all respects except for the values of certain model parameters. This is accomplished by building uncertainty models for assays belonging to two categories--substrate assays based on optical absorbance analysis of endpoint reactions, and ion selective electrode (ISE) assays based on potentiometric measurements of electromotive force., Results: Uncertainty models for the substrate assays and the ISE assays are built, and for each category, a general mathematical framework for the uncertainty model is developed. The parameters of the general framework that vary from assay to assay for each category are identified and listed., Conclusions: Estimates of measurement uncertainty from the models were compared with estimates of uncertainty from quality control data from the clinical laboratory. We demonstrate that building a general modeling framework for each assay category and plugging in parameter values for each assay is sufficient to generate uncertainty models for an assay within a given category.
- Published
- 2013
- Full Text
- View/download PDF
43. Prospective multicenter evaluation of the Beckman Coulter Prostate Health Index using WHO calibration.
- Author
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Loeb S, Sokoll LJ, Broyles DL, Bangma CH, van Schaik RH, Klee GG, Wei JT, Sanda MG, Partin AW, Slawin KM, Marks LS, Mizrahi IA, Shin SS, Cruz AB, Chan DW, Roberts WL, and Catalona WJ
- Subjects
- Biomarkers blood, Calibration, Humans, Male, Middle Aged, Prospective Studies, World Health Organization, Prostate-Specific Antigen blood
- Abstract
Purpose: Reported prostate specific antigen values may differ substantially among assays using Hybritech® or WHO standardization. The Beckman Coulter® Prostate Health Index and [-2]proPSA are newly approved serum markers associated with prostate cancer risk and aggressiveness. We studied the influence of assay standardization on these markers., Materials and Methods: Prostate specific antigen, percent free prostate specific antigen and [-2]proPSA were measured using Hybritech calibration in 892 men from a prospective, multicenter study undergoing prostate biopsy. We calculated the Prostate Health Index using the equation, ([-2]proPSA/free prostate specific antigen) × PSA. Index performance characteristics for prostate cancer detection were then determined using recalculated WHO calibration prostate specific antigen values., Results: The median Prostate Health Index was significantly higher in men with prostate cancer than in those with negative biopsies using WHO values (47.4 vs 39.8, p <0.001). The index offered improved discrimination of prostate cancer detection on biopsy (AUC 0.704) compared to percent free or total prostate specific antigen using the WHO calibration., Conclusions: The Prostate Health Index can be calculated using Hybritech or WHO standardized assays. It significantly improved prediction of the biopsy outcome over that of percent free or prostate specific antigen alone., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
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44. Associations of candidate biomarkers of vascular disease with the ankle-brachial index and peripheral arterial disease.
- Author
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Ye Z, Ali Z, Klee GG, Mosley TH Jr, and Kullo IJ
- Subjects
- Black or African American, Aged, C-Reactive Protein analysis, Cross-Sectional Studies, Female, Fibrin Fibrinogen Degradation Products analysis, Humans, Interleukin-6 blood, Linear Models, Lipoprotein(a) blood, Male, Middle Aged, Natriuretic Peptide, Brain blood, Osteoprotegerin blood, Peptide Fragments blood, Risk Factors, White People, Ankle Brachial Index, Biomarkers blood, Peripheral Arterial Disease physiopathology
- Abstract
Background: The use of multiple biomarkers representing various etiologic pathways of atherosclerosis may improve the prediction of interindividual variation in the ankle-brachial index (ABI). To this end, we investigated associations of 47 candidate biomarkers with the ABI and presence of peripheral arterial disease (PAD) in African-Americans (AAs) and non-Hispanic whites (NHWs)., Methods: Study participants included 1,291 AAs (71.1% women, mean age, 63.4±9.3 years) and 1,152 NHWs (57.5% women, mean age 58.5±10.1 years) belonging to hypertensive sibships. Peripheral arterial disease was defined as an ABI ≤ 0.90. Circulating levels of 47 candidate biomarkers were log-transformed before analysis because of skewed distribution. Multivariate regression analyses were used to identify biomarkers associated with ABI or PAD independently of age, sex, conventional risk factors, and medication use., Results: After adjustment for covariates, higher levels of nine biomarkers were associated with a lower ABI in AAs (all P ≤ 0.005); these biomarkers were C-reactive protein (CRP), interleukin-6, tumor necrosis factor receptor-II (TNF-R II), lipoprotein(a), N-terminal pro-brain natriuretic peptide (NT-proBNP), pro-atrial natriuretic peptide, C-terminal pro-arginine vasopressin, osteoprotegerin, and fibrinogen. Three biomarkers - myeloperoxidase, NT-proBNP, and D-dimer - were associated with ABI in NHWs (all P ≤ 0.01). C-reactive protein, interleukin-6, TNF-R II, lipoprotein(a), NT-proBNP, pro-atrial natriuretic peptide, D-dimer, and fibrinogen were associated with PAD (all P ≤ 0.005) in AAs after adjustment for covariates. None of the biomarkers were independently associated with PAD in NHWs., Conclusion: A multimarker approach improved the prediction of interindividual variation in the ABI in AAs and NHWs, and improved prediction of the presence of PAD in AAs.
- Published
- 2013
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45. Analytical performance specifications: relating laboratory performance to quality required for intended clinical use.
- Author
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Dalenberg DA, Schryver PG, and Klee GG
- Subjects
- Humans, Limit of Detection, Linear Models, Models, Theoretical, Quality Control, Clinical Chemistry Tests instrumentation, Clinical Chemistry Tests standards, Laboratories standards, Medical Laboratory Science instrumentation, Medical Laboratory Science standards, Quality Assurance, Health Care methods
- Abstract
This article proposes analytic performance goals for five quality indicators: precision, trueness, linearity, detection limits, and consistency across instruments and time. We defined our goals using methods linked to clinical practice data. Goals for desirable precision and trueness are based on biological variation. Linearity goals are related to total error recommendations. Detection limit goals are derived from 0.1 percentile of patient values. Goals for consistency are derived from the variability of distributions of patient test values. Data were collected and evaluated for each of these quality indicators for 46 chemistry tests measured on the Roche cobas 8000 analyzer., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
46. Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in β cells and mice.
- Author
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Aggarwal G, Ramachandran V, Javeed N, Arumugam T, Dutta S, Klee GG, Klee EW, Smyrk TC, Bamlet W, Han JJ, Rumie Vittar NB, de Andrade M, Mukhopadhyay D, Petersen GM, Fernandez-Zapico ME, Logsdon CD, and Chari ST
- Subjects
- Adenocarcinoma pathology, Adrenomedullin drug effects, Adrenomedullin genetics, Aged, Animals, Cell Line, Tumor, Cells, Cultured, Diabetes Mellitus, Type 2 pathology, Female, Glucose pharmacology, Humans, In Vitro Techniques, Insulin metabolism, Insulin-Secreting Cells drug effects, Insulin-Secreting Cells pathology, Male, Mice, Mice, Nude, Middle Aged, Models, Animal, Pancreas metabolism, Pancreas pathology, Pancreatic Neoplasms pathology, RNA, Small Interfering pharmacology, Rats, Transplantation, Heterologous, Adenocarcinoma metabolism, Adrenomedullin metabolism, Diabetes Mellitus, Type 2 metabolism, Insulin Resistance physiology, Insulin-Secreting Cells metabolism, Pancreatic Neoplasms metabolism, Up-Regulation
- Abstract
Background & Aims: New-onset diabetes in patients with pancreatic cancer is likely to be a paraneoplastic phenomenon caused by tumor-secreted products. We aimed to identify the diabetogenic secretory product(s) of pancreatic cancer., Methods: Using microarray analysis, we identified adrenomedullin as a potential mediator of diabetes in patients with pancreatic cancer. Adrenomedullin was up-regulated in pancreatic cancer cell lines, in which supernatants reduced insulin signaling in beta cell lines. We performed quantitative reverse-transcriptase polymerase chain reaction and immunohistochemistry on human pancreatic cancer and healthy pancreatic tissues (controls) to determine expression of adrenomedullin messenger RNA and protein, respectively. We studied the effects of adrenomedullin on insulin secretion by beta cell lines and whole islets from mice and on glucose tolerance in pancreatic xenografts in mice. We measured plasma levels of adrenomedullin in patients with pancreatic cancer, patients with type 2 diabetes mellitus, and individuals with normal fasting glucose levels (controls)., Results: Levels of adrenomedullin messenger RNA and protein were increased in human pancreatic cancer samples compared with controls. Adrenomedullin and conditioned media from pancreatic cell lines inhibited glucose-stimulated insulin secretion from beta cell lines and islets isolated from mice; the effects of conditioned media from pancreatic cancer cells were reduced by small hairpin RNA-mediated knockdown of adrenomedullin. Conversely, overexpression of adrenomedullin in mice with pancreatic cancer led to glucose intolerance. Mean plasma levels of adrenomedullin (femtomoles per liter) were higher in patients with pancreatic cancer compared with patients with diabetes or controls. Levels of adrenomedullin were higher in patients with pancreatic cancer who developed diabetes compared those who did not., Conclusions: Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in β cells and mice., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2012
- Full Text
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47. Application of mathematical models of system uncertainty to evaluate the utility of assay calibration protocols.
- Author
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Ramamohan V, Abbott J, Klee GG, and Yih Y
- Subjects
- Artifacts, Calibration, Humans, Quality Control, Clinical Chemistry Tests, Models, Statistical, Uncertainty
- Abstract
Background: Laboratory protocols used to calibrate commercial clinical chemistry systems affect test result quality. Mathematical models of system uncertainty can be developed using performance parameters provided by the manufacturer for various subsystems. These models can be used to evaluate protocols for specific laboratory operations., Methods: A mathematical model was developed to estimate the uncertainty inherent in the Roche Diagnostics P-Modular system, and included uncertainties associated with the sample and reagent pipettes, spectrometer and the calibration process. The model was then used to evaluate various alternate calibration protocols: calibration based on mean of replicate measurements (n=1-6) and calibration based on conditional acceptance when the following quality control specimen was within one standard deviation of target. The effect of calibrator concentrations on assay measurement uncertainty was also studied, and calibrator concentrations that minimize uncertainty at a specific concentration were identified., Results: The simulation model produced uncertainty estimates of 3.5% for the serum cholesterol assay and identified sample pipette (40%) and spectrometer (21%) as the largest contributors to measurement uncertainty. Each additional replicate calibrator measurements result in diminishing reductions in measurement uncertainty, with maximum reductions (19%) achieved with five replicate measurements. The conditional acceptance of calibration only when the control was within 1s resulted in an 18% reduction., Conclusions: The model can be used to evaluate the utility of laboratory protocols and establish realistic assay performance targets. The model also can help instrument manufacturers and laboratorians identify major contributors to assay measurement uncertainty, which helps improve performance in future assay systems.
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- 2012
- Full Text
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48. Multi-center analytical performance evaluation of the Access Hybritech® p2PSA immunoassay.
- Author
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Sokoll LJ, Chan DW, Klee GG, Roberts WL, van Schaik RH, Arockiasamy DA, Broyles DL, Carlson CM, Mizrahi IA, Pierson TB, and Tam JE
- Subjects
- Humans, Luminescent Measurements methods, Male, Sensitivity and Specificity, Immunoassay methods, Prostate-Specific Antigen blood
- Abstract
Background: Total PSA assays measure both complexed and non-complexed forms of PSA while free PSA assays only measure non-complexed forms. Free PSA is a mixture of isoforms including immature PSA (proPSA) with retained portions of the leader sequence (e.g. [-7], [-4], and [-2]proPSA) and nicked forms (BPSA). ProPSA isoforms in male sera have been associated with prostate cancer. This study characterized the analytical performance of a chemiluminescent immunoassay for [-2]proPSA., Methods: The Access Hybritech p2PSA assay is a sandwich immunoassay using an anti-[-2]proPSA monoclonal antibody attached to paramagnetic beads and an anti-PSA monoclonal antibody conjugated to alkaline phosphatase calibrated with recombinant [-2]proPSA. Analytical studies including sensitivity (CLSI EP17-A) and imprecision (CLSI EP5-A2) were performed., Results: The Access Hybritech p2PSA assay for [-2]proPSA had a dynamic range of 0.5 to 5000 pg/ml. The total CV of the assay was <7% for [-2]proPSA concentrations between 20 and 1000 pg/ml. The LOB was 0.50 pg/ml, LOD 0.69 pg/ml, and LOQ 3.23 pg/ml (20% CV). There was no hook effect up to 15,000 pg/ml. There was a <5% difference between calibrator and reagent lots and no interference from normal serum constituents., Conclusions: The Access Hybritech p2PSA assay is a robust immunoassay for the measurement of serum [-2]proPSA., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2012
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49. Global methylation profiling for risk prediction of prostate cancer.
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Mahapatra S, Klee EW, Young CY, Sun Z, Jimenez RE, Klee GG, Tindall DJ, and Donkena KV
- Subjects
- Biomarkers, Tumor genetics, DNA, Neoplasm genetics, DNA, Neoplasm metabolism, Humans, Male, Middle Aged, Neoplasm Recurrence, Local genetics, Prognosis, Promoter Regions, Genetic, Prostatic Neoplasms diagnosis, DNA Methylation, DNA, Neoplasm chemistry, Neoplasm Recurrence, Local diagnosis, Prostatic Neoplasms genetics
- Abstract
Purpose: The aim of this study was to investigate the promoter hypermethylation as diagnostic markers to detect malignant prostate cells and as prognostic markers to predict the clinical recurrence of prostate cancer., Experimental Design: DNA was isolated from prostate cancer and normal adjacent tissues. After bisulfite conversion, methylation of 14,495 genes was evaluated using the Methylation27 microarrays in 238 prostate tissues. We analyzed methylation profiles in four different groups: (i) tumor (n = 198) versus matched normal tissues (n = 40), (ii) recurrence (n = 123) versus nonrecurrence (n = 75), (iii) clinical recurrence (n = 80) versus biochemical recurrence (n = 43), and (iv) systemic recurrence (n = 36) versus local recurrence (n = 44). Group 1, 2, 3, and 4 genes signifying biomarkers for diagnosis, prediction of recurrence, clinical recurrence, and systemic progression were determined. Univariate and multivariate analyses were conducted to predict risk of recurrence. We validated the methylation of genes in 20 independent tissues representing each group by pyrosequencing., Results: Microarray analysis revealed significant methylation of genes in four different groups of prostate cancer tissues. The sensitivity and specificity of methylation for 25 genes from 1, 2, and 4 groups and 7 from group 3 were shown. Validation of genes by pyrosequencing from group 1 (GSTP1, HIF3A, HAAO, and RARβ), group 2 (CRIP1, FLNC, RASGRF2, RUNX3, and HS3ST2), group 3 (PHLDA3, RASGRF2, and TNFRSF10D), and group 4 (BCL11B, POU3F3, and RASGRF2) confirmed the microarray results., Conclusions: Our study provides a global assessment of DNA methylation in prostate cancer and identifies the significance of genes as diagnostic and progression biomarkers of prostate cancer., (©2012 AACR.)
- Published
- 2012
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50. Candidate serum biomarkers for prostate adenocarcinoma identified by mRNA differences in prostate tissue and verified with protein measurements in tissue and blood.
- Author
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Klee EW, Bondar OP, Goodmanson MK, Dyer RB, Erdogan S, Bergstralh EJ, Bergen HR 3rd, Sebo TJ, and Klee GG
- Subjects
- Adenocarcinoma metabolism, Biomarkers, Tumor metabolism, Enzyme-Linked Immunosorbent Assay, Humans, Immunohistochemistry, Male, Prostatic Neoplasms metabolism, Tandem Mass Spectrometry, Adenocarcinoma blood, Adenocarcinoma genetics, Biomarkers, Tumor blood, Biomarkers, Tumor genetics, Prostatic Neoplasms blood, Prostatic Neoplasms genetics, RNA, Messenger genetics
- Abstract
Background: Improved tests are needed for detection and management of prostate cancer. We hypothesized that differential gene expression in prostate tissue could help identify candidate blood biomarkers for prostate cancer and that blood from men with advanced prostate disease could be used to verify the biomarkers presence in circulation., Methods: We identified candidate markers using mRNA expression patterns from laser-capture microdissected prostate tissue and confirmed tissue expression using immunohistochemistry (IHC) for the subset of candidates having commercial antisera. We analyzed tissue extracts with tandem mass spectrometry (MS/MS) and measured blood concentrations using immunoassays and MS/MS of trypsin-digested, immunoextracted peptides., Results: We selected 35 novel candidate prostate adenocarcinoma biomarkers. For all 13 markers having commercial antisera for IHC, tissue expression was confirmed; 6 showed statistical discrimination between nondiseased and malignant tissue, and only 5 were detected in tissue extracts by MS/MS. Sixteen of the 35 candidate markers were successfully assayed in blood. Four of 8 biomarkers measured by ELISA and 3 of 10 measured by targeted MS showed statistically significant increases in blood concentrations of advanced prostate cancer cases, compared with controls., Conclusions: Seven novel biomarkers identified by gene expression profiles in prostate tissue were shown to have statistically significant increased concentrations in blood from men with advanced prostate adenocarcinoma compared with controls: apolipoprotein C1, asporin, cartilage oligomeric matrix protein, chemokine (C-X-C motif) ligand 11 (CXCL11), CXCL9, coagulation factor V, and proprotein convertase subtilisin/kexin 6.
- Published
- 2012
- Full Text
- View/download PDF
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