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Cited by 718Diabetes Management and ResearchDiabetes Treatment and ManagementClinical Laboratory Practices and Quality Control

Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus

Open access
Sacks, David B., Arnold, Mark, Bakris, George L., Bruns, David E., Horvath, Andrea Rita, Kirkman, M. Sue, Lernmark, Ake, Metzger, Boyd E. +1 more·2011·Diabetes Care
DOI 10.2337/dc11-9998PMC PMC3114322
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Abstract

BACKGROUND: Multiple laboratory tests are used to diagnose and manage patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these tests varies substantially. APPROACH: An expert committee compiled evidence-based recommendations for the use of laboratory testing for patients with diabetes. A new system was developed to grade the overall quality of the evidence and the strength of the recommendations. Draft guidelines were posted on the Internet and presented at the 2007 Arnold O. Beckman Conference. The document was modified in response to oral and written comments, and a revised draft was posted in 2010 and again modified in response to written comments. The National Academy of Clinical Biochemistry and the Evidence-Based Laboratory Medicine Committee of the American Association for Clinical Chemistry jointly reviewed the guidelines, which were accepted after revisions by the Professional Practice Committee and subsequently approved by the Executive Committee of the American Diabetes Association. CONTENT: In addition to long-standing criteria based on measurement of plasma glucose, diabetes can be diagnosed by demonstrating increased blood hemoglobin A1c (HbA1c) concentrations. Monitoring of glycemic control is performed by self-monitoring of plasma or blood glucose with meters and by laboratory analysis of HbA1c. The potential roles of noninvasive glucose monitoring, genetic testing, and measurement of autoantibodies, urine albumin, insulin, proinsulin, C-peptide, and other analytes are addressed. SUMMARY: The guidelines provide specific recommendations that are based on published data or derived from expert consensus. Several analytes have minimal clinical value at present, and their measurement is not recommended.

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Crossref · 10.2337/dc11-9998

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Claims the paper makes

0 of 387 cited sources checked · 0 supported · 0 flagged

  • Findingreasoning

    The important causal role of hyperglycemia in the development and progression of complications has been documented in clinical trials.

    “The important causal role of hyperglycemia in the development and progression of complications has been documented in clinical trials.”
    Quote in the paperSubstantial claim
  • Findingcitation

    The published literature lacks consensus as to which screening procedure (FPG, OGTT, and/or HbA1c) is the most appropriate.

    “In addition, the published literature lacks consensus as to which screening procedure (FPG, OGTT, and/ or HbA 1c ) is the most appropriate (20,(28)(29)(30).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [20] The International Expert Committee, 2009, International Expert Committee report on the role of the A1c assay in the diagnosis of diabetes, Diabetes Care source

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    • cites [28] Icks, 2005, Cost-effectiveness of type 2 diabetes screening: results from recently published studies, Gesundheitswesen source

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    • cites [29] Perry, 2001, HbA1c measurement improves the detection of type 2 diabetes in high-risk individuals with nondiagnostic levels of fasting plasma glucose: the Early Diabetes Intervention Program (EDIP), Diabetes Care source

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  • Findingcitation

    Longer follow-up documented a significant reduction in cardiovascular disease in patients with type 1 diabetes treated with intensive glycemic control.

    “Longer follow-up documented a significant reduction in cardiovascular disease in patients with type 1 diabetes treated with intensive glycemic control (45).”
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    • cites [45] Nathan, 2005, Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes, N Engl J Med source

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  • Findingcitation

    Intensive plasma glucose control significantly reduced microvascular complications in patients with type 2 diabetes.

    “Intensive plasma glucose control significantly reduced microvascular complications in patients with type 2 diabetes.”
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    • cites [46] UKPDS Group, 1998, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33), Lancet source

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  • Findingnone given

    There is no published evidence that treatment based on screening has an effect on long-term complications.

    “Despite these recommendations and the demonstration that interventions can delay and sometimes prevent the onset of type 2 diabetes in individuals with impaired glucose tolerance (26,27), there is as yet no published evidence that treatment based on screening has an effect on long-term complications.”
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    • cites [26] Knowler, 2002, Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin, N Engl J Med source

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    • cites [27] Tuomilehto, 2001, Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance, N Engl J Med source

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    Findingnone given

    In both the DCCT and the UKPDS, patients in the intensive-treatment group maintained lower median plasma glucose concentrations; however, analyses of the outcomes were linked to HbA1c rather than glucose concentration.

    “In both the Diabetes Control and Complications Trial (DCCT) and the UKPDS, patients in the intensive-treatment group maintained lower median plasma glucose concentrations; however, analyses of the outcomes were linked to HbA 1c , which was used to evaluate glycemic control, rather than glucose concentration.”
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    Findingcitation

    Intensive insulin therapy reduced hypercholesterolemia by 34%, but the risk of macrovascular disease was not significantly decreased in the original analysis.

    “Although intensive insulin therapy reduced hypercholesterolemia by 34%, the risk of macrovascular disease was not significantly decreased in the original analysis (44).”
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    • cites [44] DCCT, 1993, The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus, N Engl J Med source

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    Findingcitation

    The incremental cost of screening all persons ≥25 years of age has been estimated to be $236,449 per life-year gained and $56,649 per QALY gained.

    “The incremental cost of screening all persons $25 years of age has been estimated to be $236,449 per life-year gained and $56,649 per quality-adjusted lifeyear (QALY) gained (32).”
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    • cites [32] Diabetes Cost-Effectiveness Study Group, Centers for Disease Control and Prevention, 1998, The cost-effectiveness of screening for type 2 diabetes, JAMA source

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    Findingcitation

    Modeling run on 1 x 10^6 individuals suggests considerable uncertainty as to whether screening for diabetes would be cost-effective.

    “Modeling run on 1 x 10 6 individuals suggests considerable uncertainty as to whether screening for diabetes would be cost-effective (34).”
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    • cites [34] Glumer, 2006, What determines the cost-effectiveness of diabetes screening?, Diabetologia source

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    Findingcitation

    Screening targeted to individuals with hypertension reduces the QALY from $360,966 to $34,375, with ages between 55 and 75 years being the most cost-effective.

    “In contrast, screening targeted to individuals with hypertension reduces the QALY from $360,966 to $34,375, with ages between 55 and 75 years being the most cost-effective (33).”
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    • cites [33] Hoerger, 2004, Screening for type 2 diabetes mellitus: a cost-effectiveness analysis, Ann Intern Med source

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    Findingcitation

    Published evidence reveals diurnal variation in FPG, with mean FPG higher in the morning than in the afternoon, indicating that many diabetes cases would be missed in patients seen in the afternoon.

    “Published evidence reveals diurnal variation in FPG, with the mean FPG being higher in the morning than in the afternoon, indicating that many diabetes cases would be missed in patients seen in the afternoon (57).”
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    • cites [57] Troisi, 2000, Diurnal variation in fasting plasma glucose: implications for diagnosis of diabetes in patients examined in the afternoon, JAMA source

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    Findingnone given

    The appropriate interval between glucose measurements in acute clinical situations is highly variable, ranging from 30 min to 24 h or more.

    “The appropriate interval between glucose measurements in acute clinical situations (e.g., patients admitted to a hospital, patients with DKA, neonatal hypoglycemia, and so forth) is highly variable and may range from 30 min to 24 h or more.”
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    Findingcitation

    The rate of glycolysis averages 5%-7%/h (approximately 0.6 mmol/L) and varies with glucose concentration, temperature, leukocyte count, and other factors.

    “The rate of glycolysisreported to average 5%-7%/h [approximately 0.6 mmol/L (10 mg/dL)] (59)-varies with the glucose concentration, temperature, leukocyte count, and other factors (60).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [59] Chan, 1989, Effectiveness of sodium fluoride as a preservative of glucose in blood, Clin Chem source

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    • cites [60] Ladenson, 1980, Nonanalytical sources of variation in clinical chemistry results

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    Findingcitation

    Loss of glucose from sample containers is a serious and underappreciated problem.

    “Loss of glucose from sample containers is a serious and underappreciated problem (58).”
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    • cites [58] Bruns, 2009, Stabilization of glucose in blood samples: why it matters, Clin Chem source

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    Findingnone given

    HbA1c values in diabetes form a continuum.

    “HbA 1c values in patients with diabetes constitute a continuum.”
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    Premisecitation

    An HbA1c, FPG, or 2-h OGTT evaluation is appropriate for screening for diabetes.

    “An HbA 1c , FPG, or 2-h OGTT evaluation is appropriate for screening (21).”
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    • cites [21] ADA, 2010, Standards of medical care in diabetes—2010, Diabetes Care

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    Premisecitation

    Type 1 diabetes mellitus is usually caused by autoimmune destruction of pancreatic islet β-cells, rendering the pancreas unable to synthesize and secrete insulin.

    “Type 1 diabetes mellitus, formerly known as insulindependent diabetes mellitus (IDDM) or juvenile-onset diabetes mellitus, is usually caused by autoimmune destruction of the pancreatic islet b-cells, rendering the pancreas unable to synthesize and secrete insulin (2).”
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    • cites [2] Castano, 1990, Type-I diabetes: a chronic autoimmune disease of human, mouse, and rat, Annu Rev Immunol source

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    Premisenone given

    Monitoring of glycemic control is performed by self-monitoring of plasma or blood glucose with meters and by laboratory analysis of HbA1c.

    “Monitoring of glycemic control is performed by self-monitoring of plasma or blood glucose with meters and by laboratory analysis of HbA 1c .”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    The diagnosis of diabetes is established by identifying the presence of hyperglycemia.

    “The diagnosis of diabetes is established by identifying the presence of hyperglycemia.”
    Quote in the paperSubstantial claim

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    Premisecitation

    In 2009, the International Expert Committee recommended that diabetes be diagnosed by measurement of HbA1c.

    “In 2009, the International Expert Committee (20), which comprised members appointed by the ADA, the European Association for the Study of Diabetes, and the IDF, recommended that diabetes be diagnosed by measurement of hemoglobin A 1c (HbA 1c ), which reflects long-term blood glucose concentrations (see HbA 1c section below).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] The International Expert Committee, 2009, International Expert Committee report on the role of the A1c assay in the diagnosis of diabetes, Diabetes Care source

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    Premisecitation

    Testing to detect type 2 diabetes in asymptomatic people is now recommended for those at risk of developing the disease.

    “Testing to detect type 2 diabetes in asymptomatic people, previously controversial, is now recommended for those at risk of developing the disease (21,22).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [21] ADA, 2010, Standards of medical care in diabetes—2010, Diabetes Care

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    • cites [22] ADA, 2001, Tests of glycemia in diabetes, Diabetes Care

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The IDF recommends that each country's health service decide whether to implement screening for diabetes, with FPG as the suggested test.

    “The IDF recommends that the health service in each country decide whether to implement screening for diabetes (23).FPG is the suggested test.”
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    • cites [23] IDF, 2005

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    Premisecitation

    If any one of the three diagnostic criteria is met, confirmation by repeat testing on a subsequent day is necessary to establish the diagnosis, except for patients with unequivocal hyperglycemia.

    “If any one of these three criteria is met, confirmation by repeat testing on a subsequent day is necessary to establish the diagnosis [note that repeat testing is not required for patients who have unequivocal hyperglycemia, i.e., .11.1 mmol/L (200 mg/dL) with symptoms consistent with hyperglycemia].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] ADA, 1997, Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, Diabetes Care source

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    Premisecitation

    The ADA proposes that all asymptomatic people ≥45 years of age be screened in a healthcare setting.

    “The ADA proposes that all asymptomatic people $45 years of age be screened in a healthcare setting.”
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    • cites [21] ADA, 2010, Standards of medical care in diabetes—2010, Diabetes Care

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    Premisecitation

    In 2003, the ADA lowered the threshold for 'normal' FPG from <6.1 mmol/L to <5.6 mmol/L.

    “In 2003, the ADA lowered the threshold for”
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    • cites [37] Genuth, 2003, Follow-up report on the diagnosis of diabetes mellitus, Diabetes Care source

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    Premisecitation

    The change in FPG threshold has been contentious and has not been accepted by all organizations.

    “This change has been contentious and has not been accepted by all organizations (19,38).”
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    • cites [19] WHO, 2006

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    • cites [38] Forouhi, 2006, The threshold for diagnosing impaired fasting glucose: a position statement by the European Diabetes Epidemiology Group, Diabetologia source

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    Premisecitation

    Type 2 diabetes mellitus is caused by a combination of insulin resistance and inadequate insulin secretion.

    “Type 2 diabetes mellitus, formerly known as non-IDDM or adultonset diabetes, is caused by a combination of insulin resistance and inadequate insulin secretion (3,4).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] Reaven, 1988, Banting Lecture 1988. Role of insulin resistance in human disease, Diabetes source

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    • cites [4] Sacks, 1996, The pathogenesis of type II diabetes mellitus. A polygenic disease, Am J Clin Pathol source

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    Premisecitation

    The International Expert Committee and the ADA have recommended that HbA1c can be used for screening for diabetes.

    “In contrast, the International Expert Committee and the ADA have recommended that HbA 1c can be used for screening for diabetes (20,21,24) (see section on HbA 1c In the absence of unequivocal hyperglycemia, these criteria should be confirmed by repeat testing.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [20] The International Expert Committee, 2009, International Expert Committee report on the role of the A1c assay in the diagnosis of diabetes, Diabetes Care source

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    • cites [21] ADA, 2010, Standards of medical care in diabetes—2010, Diabetes Care

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    • cites [24] Saudek, 2008, A new look at screening and diagnosing diabetes mellitus, J Clin Endocrinol Metab source

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    Premisecitation

    The WHO and IDF recommend either an FPG test or a 2-h postload glucose test using the same cutoffs as the ADA.

    “The WHO and the International Diabetes Federation (IDF) recommend either an FPG test or a 2-h postload glucose test that uses the same cutoffs as the ADA (19) (Table 5).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] WHO, 2006

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    Premisecitation

    An IFCC working group recommended that glucose meters report plasma glucose concentration irrespective of sample type or technology.

    “An IFCC working group recommended that glucose meters report the plasma glucose concentration, irrespective of the sample type or technology (119,120).”
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    • cites [119] Burnett, 2001, IFCC recommendation on reporting results for blood glucose, Clin Chim Acta source

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    • cites [120] D'Orazio, 2005, Approved IFCC recommendation on reporting results for blood glucose (abbreviated), Clin Chem source

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  • May combine two claims.

    Premisecitation

    Important variables that may influence bedside glucose monitoring results include changes in hematocrit, altitude, environmental temperature or humidity, hypotension, hypoxia, high triglyceride concentrations, and various drugs.

    “Important variables that may influence the results of bedside glucose monitoring include changes in hematocrit (114), altitude, environmental temperature or humidity, hypotension, hypoxia and high triglyceride concentrations (115), and various drugs.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [114] Tang, 2000, Effects of different hematocrit levels on glucose measurements with handheld meters for point-of-care testing, Arch Pathol Lab Med source

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    • cites [115] ADA, 1994, Consensus statement on self-monitoring of blood glucose, Diabetes Care source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The ADA, WHO, and IDF recommend confirming an increased FPG or abnormal OGTT result to establish diabetes diagnosis.

    “The ADA, WHO, and IDF recommend that an increased FPG or an abnormal OGTT result must be confirmed to establish the diagnosis of diabetes (19,89).”
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    • cites [19] WHO, 2006

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    • cites [89] ADA, 2009, Standards of medical care in diabetes—2009, Diabetes Care

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  • May combine two claims.

    Premisecitation

    The risk of hypoglycemia is seen primarily in patients treated with insulin or insulin secretagogues and increases substantially with tight glycemic control.

    “The risk of hypoglycemia is seen primarily in patients treated with insulin or insulin secretagogues, and it increases substantially when pharmacologic therapy is directed towards maintaining the glycemic concentrations as close to those found in nondiabetic individuals as is safely possible (44,46).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [44] DCCT, 1993, The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus, N Engl J Med source

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    • cites [46] UKPDS Group, 1998, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33), Lancet source

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  • May combine two claims.

    Interpretationreasoning

    SMBG can be useful for detecting asymptomatic hypoglycemia and allowing patients to avoid major hypoglycemic episodes.

    “SMBG can be useful for detecting asymptomatic hypoglycemia and allowing patients to avoid major hypoglycemic episodes.”
    Quote in the paperSubstantial claim

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    Premisecitation

    The onset of type 2 diabetes is estimated to occur approximately 4-7 years (or more) before clinical diagnosis, and complications may begin several years before clinical diagnosis.

    “The onset of type 2 diabetes is estimated to occur approximately 4-7 years (or more) before clinical diagnosis (56), and epidemiologic evidence indicates that complications may begin several years before clinical diagnosis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Harris, 1993, Undiagnosed NIDDM: clinical and public health issues, Diabetes Care source

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    Premisecitation

    Recurrent education at clinic visits and comparison of SMBG with concurrent laboratory glucose analysis improved the accuracy of patients' blood glucose readings.

    “Recurrent education at clinic visits and comparison of SMBG with concurrent laboratory glucose analysis improved the accuracy of patients' blood glucose readings (118).”
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    • cites [118] Kabadi, 1994, The effect of recurrent practice at home on the acceptability of capillary blood glucose readings. Accuracy of self blood glucose testing, Diabetes Care source

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    Interpretationcitation

    Reporting plasma glucose by meters can improve harmonization and allow comparison with laboratory-generated results.

    “This approach can improve harmonization and allow comparison with laboratorygenerated results (121).”
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    • cites [121] Steffes, 2005, Measurement of circulating glucose concentrations: The time is now for consistency among methods and types of samples, Clin Chem source

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    Premisecitation

    The ESMON trial found no benefit of SMBG on glycemic control but higher depression subscale scores in newly diagnosed non-insulin-treated diabetes.

    “The later ESMON study (109), a randomized controlled trial of SMBG in newly diagnosed people with diabetes not treated with insulin, found no benefit of SMBG on glycemic control but did find higher scores on a depression subscale.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [109] O'Kane, 2008, Efficacy of self monitoring of blood glucose in patients with newly diagnosed type 2 diabetes (ESMON study): randomised controlled trial, BMJ source

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    Premisecitation

    There was insufficient evidence to evaluate whether SMBG improves quality of life, well-being, patient satisfaction, or decreases hypoglycemic episodes.

    “There was insufficient evidence to evaluate whether it was beneficial in improving quality of life, improving well-being or patient satisfaction, or decreasing the number of hypoglycemic episodes.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [105] Welschen, 2005, Self-monitoring of blood glucose in patients with type 2 diabetes who are not using insulin, Cochrane Database Syst Rev source

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    • cites [106] Welschen, 2005, Self-monitoring of blood glucose in patients with type 2 diabetes who are not using insulin: a systematic review, Diabetes Care source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    It is estimated that 40% of people in the U.S. with type 2 diabetes are undiagnosed.

    “Furthermore, it is estimated that 40% of people in the U.S. with type 2 diabetes are undiagnosed (8).”
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    • cites [8] Cowie, 2009, Full accounting of diabetes and pre-diabetes in the U.S. population in 1988–1994 and 2005–2006, Diabetes Care source

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  • Classified as probably not a substantial claim.

    Premisecitation

    The efficacy of SMBG in type 2 diabetes is questionable according to the review's authors.

    “The review's authors concluded that the efficacy of SMBG in type 2 diabetes is questionable (96).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] Faas, 1997, The efficacy of self-monitoring of blood glucose in NIDDM subjects. A criteria-based literature review, Diabetes Care source

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  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Frequent SMBG is particularly important for tight glycemic control in type 1 diabetes.

    “Frequent SMBG is particularly important for tight glycemic control in type 1 diabetes.”
    Quote in the paperSubstantial claim

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    Premisecitation

    An analysis of published studies of glucose meters found deficiencies in study design, methodology, and reporting, raising the possibility that reported total error underestimates true total error.

    “an analysis of published studies of glucose meters demonstrated that the studies suffered from deficiencies in study design, methodology, and reporting (134), raising the possibility that the reported total error underestimates the true total error of the meters.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] Mahoney, 2007, Assessing the quality of glucose monitor studies: a critical evaluation of published reports, Clin Chem source

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    Premisecitation

    Evaluations of nine brands of meters in Norway showed three did not meet ISO criteria and none met 1996 ADA criteria in patients' hands.

    “Results of evaluations of nine brands of meters according to this method showed that three of nine meters did not meet the ISO criteria, and none met the 1996 ADA criteria in the hands of patients (135).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [135] Kristensen, 2004, Standardized evaluation of instruments for self-monitoring of blood glucose by patients and a technologist, Clin Chem source

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  • May combine two claims.

    Premisecitation

    In 226 hospitals, 45.6%, 25%, and 14% of split samples differed by >10%, >15%, and >20%, respectively.

    “Another study that evaluated meter performance in 226 hospitals with split samples analyzed simultaneously on meters and laboratory glucose analyzers revealed that 45.6%, 25%, and 14% of the split samples differed from each other by .10%,.15%,and .20%,respectively (131).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [131] Novis, 1998, Interinstitutional comparison of bedside blood glucose monitoring program characteristics, accuracy performance, and quality control documentation: a College of American Pathologists Q-Probes study of bedside blood glucose monitoring performed in 226 small hospitals, Arch Pathol Lab Med

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  • May combine two claims.

    Premisecitation

    The van den Berghe study used a precise and accurate glucose analyzer and arterial blood samples, whereas subsequent studies often used glucose meters and capillary finger-stick samples.

    “A Clinical Chemistry Perspective article (137) pointed out that the study of van den Berghe et al. used a precise and accurate glucose analyzer and collected arterial blood samples, whereas subsequent studies often used glucose meters and capillary blood samples obtained by finger stick.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [137] Scott, 2009, Tight glucose control in the intensive care unit: Are glucose meters up to the task?, Clin Chem source

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  • May combine two claims.

    Premisecitation

    A meta-analysis of multiple randomized controlled trials of tight glucose control conducted 7 years later failed to identify improved outcomes but found increased hypoglycemia.

    “A meta-analysis of multiple randomized controlled trials of tight glucose control conducted 7 years later failed to identify any improved outcomes but did find an increased incidence of hypoglycemia (136).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [136] Wiener, 2008, Benefits and risks of tight glucose control in critically ill adults: a meta-analysis, JAMA source

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  • May combine two claims.

    Premisecitation

    The 2003 ISO recommendations propose that for readings >4.2 mmol/L, discrepancy between meters and accredited laboratory should be <20%; for readings ≤4.2 mmol/L, discrepancy should not exceed 0.83 mmol/L in 95% of samples.

    “The 2003 International Organization for Standardization (ISO) recommendations (127) propose that for test readings .4.2 mmol/L (75 mg/dL), the discrepancy between meters and an accredited laboratory should be ,20%; for glucose readings #4.2 mmol/L (75 mg/dL), the discrepancy should not exceed 0.83 mmol/L (15 mg/dL) in 95% of the samples.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [127] ISO, 2003

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  • May combine two claims.

    Interpretationreasoning

    Errors of 20% can lead to errors in insulin dosing, which can lead to hypoglycemia.

    “errors of 20% can lead to errors in insulin dosing, which, when combined with other factors, can lead to hypoglycemia.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    Using the new gestational diabetes criteria substantially increases the incidence of gestational diabetes, mainly because only one elevated glucose value is required for diagnosis.

    “Using the new criteria substantially increases the incidence of GDM, mainly because only one increased glucose value is required to diagnose GDM (prior recommendations required two increased glucose concentrations).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The CLSI recommendations are that for 95% of samples, the difference between meter and laboratory glucose measurements be <20% when laboratory glucose >5.5 mmol/L and <0.83 mmol/L when laboratory glucose ≤5.5 mmol/L.

    “The less stringent CLSI (formerly NCCLS) recommendations are that, for 95% of the samples, the difference between meter and laboratory measurements of glucose be 1) ,20% when the laboratory glucose value is .5.5 mmol/L (100 mg/dL) and 2) ,0.83 mmol/L (15 mg/dL) of the laboratory glucose value when the glucose concentration is #5.5 mmol/L (100 mg/dL) (126).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] NCCLS, 1994, Ancillary (bedside) blood glucose testing in acute and chronic care facilities; approved guideline C30-A, Villanova (PA): NCCLS

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The nitroprusside method measures only acetoacetate unless the reagent contains glycine, in which case acetone is also measured.

    “The nitroprusside method measures only AcAc unless the reagent contains glycine, in which case acetone is also measured.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [181] Sacks, 2012, Diabetes mellitus source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The DCCT reference is an HPLC cation-exchange method that quantifies HbA1c and is a CLSI-designated comparison method.

    “The DCCT reference is an HPLC cation-exchange method that quantifies HbA 1c ; this method is a CLSI-designated comparison method (217).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [217] DCCT, 1987, Feasibility of centralized measurements of glycated hemoglobin in the Diabetes Control and Complications Trial: a multicenter study, Clin Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HbA1c is used both as an index of mean glycemia and as a measure of risk for diabetes complications.

    “HbA 1c is used both as an index of mean glycemia and as a measure of risk for the development of diabetes complications (147,197).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [147] Goldstein, 2004, Tests of glycemia in diabetes, Diabetes Care source

      Not checked in the free run.

    • cites [197] ADA, 2000, Implications of the Diabetes Control and Complications Trial [Position statement], Diabetes Care

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Several studies have shown a close mathematical relationship between HbA1c concentration and mean glycemia, which should allow HbA1c to be expressed as estimated average glucose.

    “Several studies have demonstrated a close mathematical relationship between HbA 1c concentration and mean glycemia, which should allow the expression of HbA 1c as an estimated average glucose (eAG) concentration (205,(207)(208)(209).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [205] Svendsen, 1982, Glycosylated haemoglobin and steady-state mean blood glucose concentration in type 1 (insulin-dependent) diabetes, Diabetologia

      Not checked in the free run.

    • cites [207] Murata, 2004, Contributions of weekly mean blood glucose values to hemoglobin A1c in insulin-treated type 2 diabetes: the Diabetes Outcomes in Veterans Study (DOVES), Am J Med Sci source

      Not checked in the free run.

    • cites [208] Nathan, 2007, Relationship between glycated haemoglobin levels and mean glucose levels over time, Diabetologia source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An analysis of 11,092 adults showed that blacks had mean HbA1c values 0.4% higher than whites, but race did not modify the association between HbA1c and adverse cardiovascular outcomes or death.

    “A recent analysis of 11,092 adults showed that blacks had mean HbA 1c values 0.4% higher than whites (229); however, race did not modify the association between HbA 1c concentration and adverse cardiovascular outcomes or death (229).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [229] Selvin, 2010, Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    Although clinical values from assays standardized with the new IFCC method correlate tightly with NGSP values, the absolute HbA1c values reported differ by 1.5% to 2.0% HbA1c.

    “Although the clinical values obtained with assays standardized with the new IFCC method correlate tightly with NGSP values, the absolute HbA 1c values reported differ by 1.5%-2.0%HbA 1c .”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The DCCT reference assay method has been used since 1978 and has demonstrated good long-term precision, with between-run coefficients of variation consistently below 3%.

    “The assay method has been used since 1978 and has demonstrated good long-term precision (between-run CVs are consistently ,3%) (216).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [216] Little, 2001, The National Glycohemoglobin Standardization Program: a five-year progress report, Clin Chem

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HbA1c results are not significantly affected by acute blood glucose fluctuations such as illness or meals, but age and race reportedly influence HbA1c.

    “HbA 1c results are not affected significantly by acute fluctuations in blood glucose concentrations, such as those occurring with illness or after meals; however, age and race reportedly influence HbA 1c .”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The clinical utility of glycated proteins other than hemoglobin has not been clearly established, and there is no convincing evidence linking their concentrations to chronic diabetes complications.

    “The clinical utility of glycated proteins other than Hb has not been clearly established, however, and there is no convincing evidence that relates their concentrations to the chronic complications of diabetes (147,187).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [147] Goldstein, 2004, Tests of glycemia in diabetes, Diabetes Care source

      Not checked in the free run.

    • cites [187] ADA, 2000, Tests of glycemia in diabetes [Position statement], Diabetes Care

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Diabetic ketoacidosis is most commonly associated with type 1 diabetes but may occur rarely in type 2 diabetes.

    “Although DKA is most commonly associated with type 1 diabetes, it may occur rarely in type 2 diabetic patients (193).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [193] Westphal, 1996, The occurrence of diabetic ketoacidosis in non-insulin-dependent diabetes and newly diagnosed diabetic adults, Am J Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In 1997, the IFCC formed a committee to develop a higher-order reference method and reference materials for HbA1c analysis, and the method was approved in 2001.

    “In 1997, the IFCC formed a committee to develop a higher-order reference method and reference materials for HbA 1c analysis; the method was approved in 2001 (219,220).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [219] Jeppsson, 2002, Approved IFCC reference method for the measurement of HbA1c in human blood, Clin Chem Lab Med source

      Not checked in the free run.

    • cites [220] Hoelzel, 2004, IFCC reference system for measurement of hemoglobin A1c in human blood and the national standardization schemes in the United States, Japan, and Sweden: a method-comparison study, Clin Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Those HbA1c targets are valid only for assays certified as traceable to the DCCT reference, whose reference interval is about 4-6% (20-42 mmol/mol).

    “These HbA 1c values apply only to assay methods that have been certified as traceable to the DCCT reference, with a reference interval of approximately 4%-6% HbA 1c (20-42 mmol/mol).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Other international groups, including the IDF, are considering HbA1c for diabetes diagnosis and screening.

    “Other international organizations, including the IDF, are considering HbA 1c testing for diabetes diagnosis and screening.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    The optimal frequency for diagnostic HbA1c testing is not established, though guidelines similar to glucose-based testing appear reasonable.

    “The frequency of HbA 1c testing for diagnosis has not been established, but guidelines similar to those for glucose-based testing seem appropriate.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The frequency of HbA1c testing for diagnosis has not been established.

  • Classified as probably not a substantial claim.

    Premisereasoning

    The Committee considered technical advantages of HbA1c over glucose testing, including preanalytical stability and lower biological variation.

    “In making its recommendation, the Committee also considered several technical advantages of HbA 1c testing compared with glucose testing, such as its preanalytical stability and decreased biological variation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The ADA, The Endocrine Society, and WHO have endorsed HbA1c for diabetes diagnosis.

    “The ADA has endorsed the use of HbA 1c for the diagnosis of diabetes (Table 4) (21), as have The Endocrine Society (255) and the WHO.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [21] ADA, 2010, Standards of medical care in diabetes—2010, Diabetes Care

      Not checked in the free run.

    • cites [255] American Association of Clinical Endocrinologists Board of Directors/American College of Endocrinologists Board of Trustees, 2010, American Association of Clinical Endocrinologists/American College of Endocrinology statement on the use of hemoglobin A1c for the diagnosis of diabetes, Endocr Pract source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Recent trials in type 2 diabetes that targeted HbA1c below 6.5% with multiple drugs showed inconsistent benefits and no macrovascular advantage over strategies leaving HbA1c 0.8-1.1% higher.

    “recent studies that used multiple medications to treat type 2 diabetes and aimed for HbA 1c concentrations ,6.5% (48 mmol/mol) have not demonstrated consistent benefits and failed to observe any benefit with regard to macrovascular disease, compared with interventions that achieved HbA 1c values 0.8% to 1.1% higher (50)(51)(52).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [50] Gerstein, 2008, Effects of intensive glucose lowering in type 2 diabetes, N Engl J Med source

      Not checked in the free run.

    • cites [51] Patel, 2008, Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes, N Engl J Med source

      Not checked in the free run.

    • cites [52] Duckworth, 2009, Glucose control and vascular complications in veterans with type 2 diabetes, N Engl J Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The American Association of Clinical Endocrinologists supports HbA1c for diagnosis in a more limited way.

    “The American Association of Clinical Endocrinologists supports it in a more limited fashion.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Without well-controlled studies defining a protocol, expert opinion recommends HbA1c testing at least twice yearly for stable patients at goal and quarterly for those whose therapy changed or who are not at goal.

    “In the absence of well-controlled studies that suggest a definite testing protocol, expert opinion recommends HbA 1c testing “at least two times a year in patients who are meeting treatment goals (and who have stable glycemic control) . . .and quarterly in patients whose therapy has changed or who are not meeting glycemic goals” (21).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] ADA, 2010, Standards of medical care in diabetes—2010, Diabetes Care

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The labile Schiff base forms quickly under high glucose and may interfere with certain HbA1c assays unless fully removed or separated.

    “This Schiff base is formed rapidly with hyperglycemia and can interfere with some HbA 1c assay methods if it is not completely removed or separated.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [248] Goldstein, 1980, Effects of acute changes in blood glucose on HbA1c, Diabetes source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisereasoning

    The convenience of HbA1c testing, with no fasting or tolerance test needed, persuaded the Committee to recommend it for diagnosis.

    “Finally, the clinical convenience of the HbA 1c assay, which requires no patient fasting or tolerance tests, compared with glucose-based diagnosis, convinced the Committee to recommend HbA 1c testing for diagnosis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    For most HbA1c methods, whole-blood samples stored at -70°C or colder are stable for at least one year, but samples are not as stable at -20°C.

    “For most methods, whole-blood samples stored at 270°C or colder are stable over the long term (at least 1 year), but samples are not as stable at 220°C.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The ADA, mainly based on DCCT, recommends a primary treatment target of HbA1c below 7% (53 mmol/mol).

    “Principally on the basis of the DCCT results, the ADA has recommended that a primary goal of therapy be an HbA 1c value ,7% (53 mmol/mol) (21).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] ADA, 2010, Standards of medical care in diabetes—2010, Diabetes Care

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intraindividual coefficients of variation for healthy persons are very small, below 2%, and many current HbA1c assays achieve intralaboratory and interlaboratory coefficients of variation below 2% and 3%, respectively.

    “Intraindividual CVs for healthy persons are very small (,2%), and many current assay methods can achieve intralaboratory and interlaboratory CVs of ,2% and ,3%, respectively (247).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [247] Sacks, 2010, CAP surveys: participant summary for glycohemoglobin survey 2010 set GH2-A, Northfield, IL

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    Having HbA1c results ready at the clinic visit can be achieved by pre-visit mailed samples or by a convenient rapid-assay system.

    “It is possible to achieve the goal of having HbA 1c test results available at the time of the clinic visit by either having the patient send in a blood sample shortly before the scheduled clinic visit or having a rapid-assay system convenient to the clinic.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Glucose-based testing for diagnosis remains valid.

    “Note that glucose-based testing for diagnosis remains valid.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationcitation

    People with HbA1c between 5.7% and 6.4% (39-46 mmol/mol) should be regarded as at high risk for future diabetes and counseled on risk-reduction measures.

    “Analogous to the concept of impaired fasting glucose and impaired glucose tolerance, individuals with HbA 1c values between 5.7% and 6.4% (39 and 46 mmol/mol) should be considered at high risk for future diabetes and should be counseled about effective measures to reduce their risk (93).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93] ADA, 2011, Standards of medical care in diabetes—2011, Diabetes Care

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    HbA1c formation proceeds through a Schiff base intermediate known as pre-A1c or labile A1c.

    “The formation of HbA 1c involves an intermediate Schiff base, which is called “pre-A 1c ” or “labile A 1c ” (248).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [248] Goldstein, 1980, Effects of acute changes in blood glucose on HbA1c, Diabetes source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The ADA advises that A1C testing frequency should depend on the clinical situation, treatment regimen, and clinician judgment.

    “The ADA recommends (21), “For any individual patient, the frequency of A1C testing should be dependent on the clinical situation, the treatment regimen used, and the judgment of the clinician.””
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] ADA, 2010, Standards of medical care in diabetes—2010, Diabetes Care

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The ADA states that either HbA1c or a glucose test (FPG or OGTT) may serve as the confirmatory test, but repeating the same test is preferred.

    “The ADA indicates that although either an HbA 1c assay or a glucose assay (FPG or OGTT) can be used as the confirmatory test, repeating the same test is preferred (93).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [93] ADA, 2011, Standards of medical care in diabetes—2011, Diabetes Care

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Improved NGSP and IFCC standardization plus new evidence linking HbA1c to retinopathy led the International Expert Committee to recommend HbA1c for diabetes diagnosis.

    “With improved standardization through the NGSP and the IFCC, and new data demonstrating the association between HbA 1c concentrations and the risk for retinopathy, the International Expert Committee recommended the use of HbA 1c in the diagnosis of diabetes (20).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] The International Expert Committee, 2009, International Expert Committee report on the role of the A1c assay in the diagnosis of diabetes, Diabetes Care source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Diabetes quality-assurance programs such as Provider Recognition Program and HEDIS have generally required documentation of the proportion of diabetic patients with at least one HbA1c test in the prior year.

    “Diabetes quality-assurance programs [e.g., Provider Recognition Program and HEDIS (Healthcare Effectiveness Data and Information Set) (199,200)] have generally required documentation of the percentage of diabetic patients who have had at least one HbA 1c measurement during the preceding year.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [199] Davidson, 1998, Diabetes research and diabetes care. Where do we stand?, Diabetes Care source

      Not checked in the free run.

    • cites [200] ADA, 2000, Provider Notes: the newsletter of the ADA/NCQA Provider Recognition Program, Provid Notes

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    The testing frequency recommendations apply to nonpregnant patients with type 1 or type 2 diabetes.

    “These testing recommendations are for nonpregnant patients with either type 1 or type 2 diabetes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Several point-of-care HbA1c assays are NGSP certified, but in the U.S. the test is waived and proficiency testing is not required.

    “Although several point-of-care HbA 1c assays are NGSP certified, the test is waived in the U.S., and proficiency testing is not necessary.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Blood can be obtained by venipuncture or by finger-stick capillary sampling.

    “Blood can be obtained by venipuncture or by finger-stick capillary sampling (237,238).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [237] Rendell, 1987, Fingerstick glycosylated hemoglobin, plasma protein, and albumin, Diabetes Care source

      Not checked in the free run.

    • cites [238] Ferrell, 1984, Glycosylated hemoglobin determination from capillary blood samples. Utility in an epidemiologic survey of diabetes, Am J Epidemiol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Class I molecules are made of an alpha chain and beta2-microglobulin; class II molecules have alpha and beta chains.

    “Class I molecules consist of an a chain and b 2 -microglobulin, and class II molecules have a and b chains.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Some haplotypes increase susceptibility, while others substantially delay or even protect against disease.

    “Some haplotypes induce susceptibility, however, whereas others provide significant delay or even protection.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Genetic markers have limited current clinical value in diabetes evaluation and management, but mutation analysis is emerging for classifying neonatal diabetes and MODY in young patients with dominant family history.

    “Genetic markers are currently of limited clinical value in evaluating and managing patients with diabetes; however, mutational analysis is rapidly emerging for classifying diabetes in the neonate (258-260) and in young patients with a dominant family history of diabetes, often referred to as “maturityonset diabetes of the young” (MODY) (261).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [258] Murphy, 2008, Clinical implications of a molecular genetic classification of monogenic beta-cell diabetes, Nat Clin Pract Endocrinol Metab source

      Not checked in the free run.

    • cites [259] Edghill, 2008, Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood, Diabetes source

      Not checked in the free run.

    • cites [260] Stoy, 2008, Diagnosis and treatment of neonatal diabetes: a United States experience, Pediatr Diabetes source

      Not checked in the free run.

    • cites [261] Fajans, 2001, Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young, N Engl J Med source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    HLA-DR/DQ typing can only raise or lower the probability of type 1 diabetes and is not recommended for routine diagnosis or classification.

    “Thus, HLA-DR/DQ typing can be used only to increase or decrease the probability of type 1 diabetes presentation and cannot be recommended for routine clinical diagnosis or classification (264).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [264] Nagi, 1990, The relationships of concentrations of insulin, intact proinsulin and 32–33 split proinsulin with cardiovascular risk factors in type 2 (non-insulin-dependent) diabetic subjects, Diabetologia source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Genetic screening may inform prognosis and genetic counseling, but genotype may not match phenotype.

    “Although genetic screening may provide information about prognosis and could be useful for genetic counseling, genotype may not correlate with the phenotype.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The HLA system plays a fundamental role in adaptive immunity and is genetically complex.

    “The HLA system, which has a fundamental role in the adaptive immune response, exhibits considerable genetic complexity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [275] Klein, 2000, The HLA system. First of two parts, N Engl J Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    If direct automated gene sequencing becomes standard, detection of specific diabetes mutations will likely become routine.

    “As direct automated sequencing of genes becomes standard, it is likely that the detection of specific diabetes mutations will become routine.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Recent GWAS have found more than 30 genetic factors that raise type 2 diabetes risk.

    “Recent genome-wide association studies have identified .30genetic factors that increase the risk for type 2 diabetes (272,273).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [272] Saxena, 2007, Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels, Science source

      Not checked in the free run.

    • cites [273] Scott, 2007, A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants, Science source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    The heterodimeric proteins on antigen-presenting cells, B lymphocytes, platelets, and activated T cells, but not other somatic cells, consist of cis- and trans-complemented alpha/beta chain heterodimers.

    “The heterodimeric proteins that are expressed on antigen-presenting cells, B lymphocytes, platelets, and activated T cells-but not other somatic cells-are composed of cis-and transcomplementated aand b-chain heterodimers.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisereasoning

    Serologic HLA typing should be replaced by molecular methods because mixed-specificity and cross-reactive antibodies are estimated to cause inaccurate results in about 15% of typings.

    “Serologic HLA typing should be replaced by molecular methods, because antibodies with a mixture of specificities and cross-reactivities have been estimated to give inaccurate results in approximately 15% of typings.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The HLA complex on chromosome 6 includes class I and class II genes encoding several polypeptide chains.

    “The HLA complex on chromosome 6 contains class I and class II genes that code for several polypeptide chains (275).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [275] Klein, 2000, The HLA system. First of two parts, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Several MODY genetic factors and many individual mutants have been identified.

    “Several genetic factors for MODY have been identified, and there are large numbers of individual mutants.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Besides environmental factors, interactions among multiple loci may influence quantitative traits.

    “In addition to environmental factors, interactions among multiple loci for the expression of quantitative traits may be involved.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisereasoning

    A detailed analytical review is omitted because genetic testing for diabetes outside research is not currently recommended for clinical care.

    “A detailed review of analytical issues will not be attempted here, because genetic testing for diabetes outside of a research setting is currently not recommended for clinical care.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Eight different MODY types have been identified.

    “Eight different MODYs have been identified.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    These storage conditions keep DNA integrity virtually indefinitely.

    “These conditions maintain DNA sample integrity virtually indefinitely.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    MODY severity varies by mutation: glucokinase mutations are usually mild without long-term complications, while HNF mutations can be as severe as typical type 1 diabetes.

    “Depending on the specific MODY mutation, the disease can be mild (e.g., glucokinase mutation) and not usually associated with long-term complications of diabetes, or it can be as severe as typical type 1 diabetes [e.g., hepatocyte nuclear factor (HNF) mutations] (277).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [277] Fajans, 1996, Maturity onset diabetes of the young (MODY), Diabet Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The average DNA yield is 100-200 mg from 10 mL whole blood.

    “The average yield is 100-200 mg DNA from 10 mL of whole blood.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    MODY-2 is caused by mutations in the GCK gene.

    “MODY-2 is caused by mutations in the GCK [glucokinase (hexokinase 4)] gene.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The major class I genes are HLA-A, HLA-B, and HLA-C.

    “The major (classic) class I genes are HLA-A (major histocompatibility complex, class I, A), HLA-B (major histocompatibility complex, class I, B), and HLA-C (major histocompatibility complex, class I, C).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    For general-population screening of type 1 diabetes susceptibility, HLA-D genes are most important, accounting for up to 50% of familial susceptibility.

    “For screening for the propensity for type 1 diabetes in general populations, HLA-D genes are the most important, contributing as much as 50% of familial susceptibility (278).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [278] Todd, 1997, Genetics of type 1 diabetes, Pathol Biol (Paris)

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The molecules encoded by both classes are heterodimers.

    “Both classes of the encoded molecules are heterodimers.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    MODY mutations involve nucleotide substitutions, deletions, or insertions in gene coding regions.

    “MODY mutations have substitution, deletion, or insertion of nucleotides in the coding regions of the genes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Mutation detection methods differ by mutation type.

    “Methods for the detection of mutations vary with the type of mutation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    DNA should be extracted within 3 days from EDTA blood samples, since longer delays reduce yield and degrade DNA quality.

    “Blood samples should be drawn into test tubes containing EDTA, and the DNA should be extracted within 3 days; longer periods both lower the yield and degrade the quality of the DNA obtained.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Fewer than 5% of type 2 diabetes cases have a molecular genetic explanation, and most such cases are autosomal dominant or have marked insulin resistance.

    “Fewer than 5% of patients with type 2 diabetes have been resolved on a molecular genetic basis, and, not surprisingly, most of these patients have an autosomal dominant form of the disease or very high degrees of insulin resistance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Those two haplotypes occur in 30-40% of a Caucasian population, so HLA is necessary but not sufficient for the disease.

    “These two haplotypes may be present in 30%-40% of a Caucasian population, and HLA is therefore necessary but not sufficient for disease.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    IFCC standardization, which offers a chemically discrete standard, is being implemented globally.

    “Furthermore, the IFCC standardization, which provides a chemically discrete standard, is being implemented worldwide.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Some evidence suggests early diagnosis may prevent ketoacidosis hospitalization and preserve residual beta-cells.

    “There is some evidence that early diagnosis may prevent hospitalization for ketoacidosis and preserve residual b-cells (271).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [271] Barker, 2004, Clinical characteristics of children diagnosed with type 1 diabetes through intensive screening and follow-up, Diabetes Care source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    How HNF lesions act in MODY remains unclear.

    “The modes of action of the HNF lesions in MODY are still not clear.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Mutations in HNF1A, HNF1B, and HNF4A likely cause diabetes by impairing insulin secretion.

    “It is likely that mutations in HNF1A, HNF1B, and HNF4A cause diabetes because they impair insulin secretion.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Type 2 diabetes is a heterogeneous polygenic disorder involving both insulin resistance and impaired insulin secretion.

    “Type 2 diabetes is a heterogeneous polygenic disease with both resistance to the action of insulin and defective insulin secretion (3,4).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] Reaven, 1988, Banting Lecture 1988. Role of insulin resistance in human disease, Diabetes source

      Not checked in the free run.

    • cites [4] Sacks, 1996, The pathogenesis of type II diabetes mellitus. A polygenic disease, Am J Clin Pathol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These diabetes forms may result from Prader-Willi syndrome obesity (chromosome 15q) or from absent adipose tissue in recessive Seip-Berardinelli generalized lipodystrophy (chromosome 9q34).

    “Such forms of diabetes may be secondary to the obesity associated with Prader-Willi syndrome, which maps to chromosome 15q, or to the absence of adipose tissue inherent to the recessive Seip-Berardinelli syndrome of generalized lipodystrophy, which maps to chromosome 9q34 (1,276).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] ADA, 1997, Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, Diabetes Care source

      Not checked in the free run.

    • cites [276] Taylor, 1999, Genetically defined forms of diabetes in children, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HLA-DQ genes appear central to HLA-associated type 1 diabetes risk, though HLA-DR genes may act independently.

    “HLA-DQ genes appear to be central to the HLA-associated risk of type 1 diabetes, albeit HLA-DR genes may be independently involved [for reviews, see (279,280)].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [279] Atkinson, 2001, Type 1 diabetes: new perspectives on disease pathogenesis and treatment, Lancet source

      Not checked in the free run.

    • cites [280] Harrison, 2001, Risk assessment, prediction and prevention of type 1 diabetes, Pediatr Diabetes source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    These mutations are detected using PCR.

    “These mutations are detected by the PCR.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Autoantibodies marking disease pathogenesis are often associated with HLA-DRB1, HLA-DQA1, and HLA-DQB1, suggesting self-peptides may also be presented to T cells.

    “Not only the disease but also autoantibodies, which are markers of the disease's pathogenesis, are often associated with HLA-DRB1, HLA-DQA1, and HLA-DQB1, indicating that self-peptides may also be presented to T cells (262).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [262] Graham, 2002, Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The risk alleles at these loci have small effects (odds ratios 1.1-1.3) and do not substantially improve type 2 diabetes risk prediction.

    “The risk alleles in these loci all have relatively small effects (odds ratios of 1. 1 to 1.3), however, and do not significantly enhance our ability to predict the risk of type 2 diabetes (274).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [274] Meigs, 2008, Genotype score in addition to common risk factors for prediction of type 2 diabetes, N Engl J Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    MODY-8 is caused by mutations in the CEL gene.

    “MODY-8 is due to mutations in the CEL [carboxyl ester lipase (bile salt-stimulated lipase)] gene.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    The genes are HNF4A for MODY-1, HNF1A for MODY-3, HNF1B for MODY-5, PDX1 for MODY-4, NEUROD1 for MODY-6, and KLF1 for MODY-7.

    “These genes are HNF4A (hepatocyte nuclear factor 4, alpha) in MODY-1, HNF1A (HNF1 homeobox A) in MODY-3, HNF1B (HNF1 homeobox B) in MODY-5, PDX1 (pancreatic and duodenal homeobox 1; formerly known as IPF1) in MODY-4, NEUROD1 (neurogenic differentiation 1; also known as NeuroD and BETA2) in MODY-6, and KLF1 [Kruppel-like factor 1 (erythroid)] in MODY-7.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Some pediatric diabetologists currently treat presumed type 2 diabetes children with oral drugs but start autoantibody-positive children on insulin immediately.

    “For example, some pediatric diabetologists now treat children thought to have type 2 diabetes with oral medications but treat autoantibody-positive children immediately with insulin.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    The VNTR upstream of INS on chromosome 11q helps predict type 1 diabetes, and the longest VNTR alleles are protective.

    “For example, the variable nucleotide tandem repeat (VNTR) upstream from the INS gene on chromosome 11q is useful for predicting the development of type 1 diabetes, with alleles with the longest VNTR having protective effects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    About 5-10% of adult Caucasian patients with a type 2 diabetes phenotype also have islet cell autoantibodies, especially GAD65A, which predict insulin dependency.

    “Approximately 5%-10% of adult Caucasian patients who present with a type 2 diabetes phenotype also have islet cell autoantibodies (298), particularly GAD65A, which predict insulin dependency.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [298] Turner, 1997, UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. UK Prospective Diabetes Study Group [published erratum appears in Lancet 1998;351:376], Lancet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Up to 1 in 4 women with type 1 diabetes have autoimmune thyroid disease, and 1 in 280 patients develop adrenal autoantibodies and adrenal insufficiency.

    “As many as 1 in 4 females with type 1 diabetes have autoimmune thyroid disease, whereas 1 in 280 patients develop adrenal autoantibodies and adrenal insufficiency.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Children with certain HLA-DR and/or HLA-DQB1 chains (*0602/*0603/*0301) are largely protected from type 1 diabetes but not from developing islet cell autoantibodies.

    “Children with certain HLA-DR and/ or HLA-DQB1 chains (*0602/*0603/ *0301) are mostly protected from type 1 diabetes, but not from developing islet cell autoantibodies (297).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [297] Schott, 1994, GAD65 autoantibodies increase the predictability but not the sensitivity of islet cell and insulin autoantibodies for developing insulin dependent diabetes mellitus, J Autoimmun source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Islet cell autoantibodies suggest insulin is the most appropriate therapy, particularly in young people.

    “The presence of islet cell autoantibodies suggests that insulin therapy is the most appropriate therapeutic option, especially in a young person.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Several islet cell autoantibodies occur in type 1 diabetes, but measuring them has limited use outside clinical studies.

    “Therefore, although several islet cell autoantibodies have been detected in individuals with type 1 diabetes, their measurement has limited use outside of clinical studies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Prospective studies in children show islet cell autoantibodies can be transient, so an autoantibody may vanish before hyperglycemia or diabetes symptoms begin.

    “Prospective studies of children reveal that islet cell autoantibodies may be transient, indicating that an islet autoantibody may have disappeared prior to the onset of hyperglycemia or diabetes symptoms (307).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [307] Siljander, 2009, Role of insulin autoantibody affinity as a predictive marker for type 1 diabetes in young children with HLA-conferred disease susceptibility, Diabetes Metab Res Rev source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Class II MHC molecules present antigen to CD4 helper cells; the observed associations may reflect defective affinity for islet antigenic peptides, allowing T-helper cells that escape thymic deletion to persist.

    “Class II MHC molecules are involved in antigen presentation to CD4 helper cells, and the associations outlined above are likely to be explained by defective affinities to islet cell antigenic peptides, leading to persistence of T-helper cells that escape thymic ablation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationcitation

    This progress should eventually enable family counseling, prognostic information, and selection of optimal treatments.

    “This progress should ultimately lead to family counseling, prognostic information, and the selection of optimal treatments (276,284).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [276] Taylor, 1999, Genetically defined forms of diabetes in children, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [284] Maclaren, 2001, Type 1 diabetes

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    A minority of type 1 diabetes patients (type 1B, idiopathic) have no known cause and no evidence of autoimmunity.

    “A minority of patients with type 1 diabetes (type 1B, idiopathic) have no known etiology and no evidence of autoimmunity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Relatives of type 1 diabetes patients have about a 5% risk, 15 times the general population risk of 1 in 250-300 lifetime.

    “The risk of developing type 1 diabetes in relatives of patients with the disease is approximately 5%, which is 15fold higher than the risk in the general population (1 in 250-300 lifetime risk).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] ADA, 1997, Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, Diabetes Care source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    After many years of type 1 diabetes, some antibodies become undetectable, but GAD65A usually stays elevated.

    “After years of type 1 diabetes, some antibodies fall below detection limits, but GAD65A usually remains increased.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    GAD65A-positive patients progress faster to absolute insulinopenia than antibody-negative patients, but many antibody-negative type 2 adults also eventually become insulin dependent, though more slowly.

    “Although GAD65A-positive diabetic patients progress faster to absolute insulinopenia than do antibody-negative patients, many antibody-negative (type 2) diabetic adults also progress (albeit more slowly) to insulin dependency with time.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    No acceptable therapy has been shown to prolong islet cell survival after diabetes diagnosis or to prevent clinical diabetes in autoantibody-positive people.

    “No acceptable therapy has been demonstrated to prolong the survival of islet cells once diabetes has been diagnosed or to prevent the clinical onset of diabetes in islet cell autoantibody-positive individuals (279).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [279] Atkinson, 2001, Type 1 diabetes: new perspectives on disease pathogenesis and treatment, Lancet source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The additional DR beta chains B3, B4, and B5 are not important.

    “Additional DRb chains (B3, B4, and B5) are not important.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Autoimmune beta-cell destruction has multiple genetic predispositions and is modulated by undefined environmental factors.

    “Autoimmune destruction of b-cells has multiple genetic predispositions and is modulated by undefined environmental influences.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A WHO standard exists for GAD65A and IA-2A, and their amounts are expressed in international units.

    “A WHO standard for both GAD65A and IA-2A has been established, and GAD65A and IA-2A amounts are expressed in international units (312).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [312] Mire-Sluis, 2000, The World Health Organization International Collaborative Study for islet cell antibodies, Diabetologia source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    DR molecules are also heterodimers, but the DR alpha chain is invariant across people.

    “DR molecules are heterodimers also; however, the DRa chain is invariant in all persons.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Screening relatives for islet cell autoantibodies can identify high risk, but 1-2% of healthy people have a single autoantibody to insulin, IA-2, GAD65, or ZnT8 and are at low risk.

    “Screening relatives of type 1 diabetic patients for islet cell autoantibodies can identify those at high risk for the disease; however, as many as 1%-2% of healthy individuals have a single autoantibody against insulin, IA-2, GAD65, or ZnT8 and are at low risk of developing type 1 diabetes (295).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [295] Maclaren, 1999, Only multiple autoantibodies to islet cells (ICA), insulin, GAD65, IA-2 and IA-2beta predict immune-mediated (type 1) diabetes in relatives, J Autoimmun source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    HLA-DR also affects type 1 diabetes susceptibility: DRB1*04 subtypes B1*0401 and 0405 are susceptible, while 0403 and 0406 are negatively associated even with susceptible DQA1*0301-DQB1*0302.

    “HLA-DR is also involved in susceptibility to type 1 diabetes, in that the B1*0401 and 0405 subtypes of DRB1*04 are susceptible, whereas the 0403 and 0406 subtypes are negatively associated with the disease, even when found in HLA genotypes with the susceptible DQA1*0301-DQB1*0302.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    It is possible to monitor islet cell autoantibody-positive patients until metabolic decompensation and then start insulin.

    “It is possible, however, to follow patients who are islet cell autoantibody positive to the point of metabolic decompensation and then institute insulin therapy.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Class I HLA molecules are also implicated in type 1 diabetes.

    “Class I HLA molecules are also implicated in type 1 diabetes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    For siblings of a type 1 diabetes proband, HLA-identical siblings have a 1 in 4 risk, those sharing one HLA haplotype have 1 in 12, and those sharing none have 1 in 100.

    “The risk of type 1 diabetes in HLA-identical siblings of a proband with type 1 diabetes is 1 in 4, whereas siblings who have HLA haplotype identity have a 1 in 12 risk and those with no shared haplotype have a 1 in 100 risk (280).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [280] Harrison, 2001, Risk assessment, prediction and prevention of type 1 diabetes, Pediatr Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Since islet cell autoantibodies have much lower predictive value in these children, they are often excluded from prevention trials.

    “Because islet cell autoantibodies in these individuals have substantially reduced predictive significance, they are often excluded from prevention trials.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Islet cell autoantibodies include those against islet cell cytoplasm (ICA), native insulin (IAA), IA-2bA, and three ZnT8A variants.

    “Islet cell autoantibodies comprise autoantibodies to islet cell cytoplasm (ICA), to native insulin [referred to as “insulin autoantibodies” (IAA) ( 286 and IA-2bA (also known as phogrin) (291)], and to three variants of zinc transporter 8 (ZnT8A) (292,293).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [292] Wenzlau, 2007, The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes, Proc Natl Acad Sci U S A source

      Not checked in the free run.

    • cites [293] Wenzlau, 2008, A common nonsynonymous single nucleotide polymorphism in the SLC30A8 gene determines ZnT8 autoantibody specificity in type 1 diabetes, Diabetes source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisereasoning

    Opinion is not unanimous, but islet cell autoantibodies may change therapy for some groups: Hispanic and African American children with possible nonautoimmune diabetes, adults classified as type 2 but autoantibody-positive, and children with transient hyperglycemia.

    “There is no unanimity of opinion, but the presence of islet cell autoantibodies may alter therapy for subsets of patients, including Hispanic and African American children with a potential diagnosis of nonautoimmune diabetes, adults with islet cell autoantibodies but clinically classified as type 2 diabetic, and children with transient hyperglycemia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    People heterozygous for HLA DRB1*04-DQA1*0301-DQB1*0302 and DRB1*03-DQA1*0501-DQB1*0201 are most susceptible, with about a 1 in 12 lifetime risk in the general population.

    “Thus, persons heterozygous for HLA DRB1*04-DQA1*0301-DQB1*0302 and DRB1* 03-DQA1*0501-DQB1*0201 are the most susceptible, with an absolute lifetime risk of type 1 diabetes in the general population of about 1 in 12.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Many of these patients are of African or Asian origin.

    “Many of these patients are of African or Asian origin.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Multiple islet cell autoantibodies are linked to much higher diabetes risk, but about 20% of new-onset diabetes patients produce only one autoantibody.

    “Although the production of multiple islet cell autoantibodies is associated with considerably increased diabetes risk (295,296), approximately 20% of individuals presenting with new-onset diabetes produce only a single autoantibody.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [295] Maclaren, 1999, Only multiple autoantibodies to islet cells (ICA), insulin, GAD65, IA-2 and IA-2beta predict immune-mediated (type 1) diabetes in relatives, J Autoimmun source

      Not checked in the free run.

    • cites [296] Verge, 1996, Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/ IA-2 autoantibodies, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Islet cell autoantibody testing has limited utility in type 2 diabetes because starting insulin is guided by glucose control.

    “Islet cell autoantibody testing in patients with type 2 diabetes has limited utility, because the institution of insulin therapy is based on glucose control.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The immunoturbidimetric assay is the most reliable and should be considered the standard for comparison because it has >95% sensitivity and specificity to detect very low levels of albuminuria.

    “Of the available methods, the immunoturbidimetric assay is the most reliable and should be considered the standard for comparison, because it has .95%sensitivity and specificity to detect very low levels of albuminuria.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Phase II clinical trials with alum-formulated GAD65 have reported no adverse events and some preservation of endogenous insulin production in GAD65A-positive diabetic patients.

    “Phase II clinical trials with alum-formulated GAD65 have reported no adverse events and some preservation of endogenous insulin production in GAD65A-positive diabetic patients (319,320).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [319] Agardh, 2005, Clinical evidence for the safety of GAD65 immunomodulation in adult-onset autoimmune diabetes, J Diabetes Complications source

      Not checked in the free run.

    • cites [320] Lernmark, 2005, Immunomodulation with human recombinant autoantigens, Trends Immunol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    For individuals positive for islet cell autoantibodies, HLA-DR/HLA-DQ genotyping will help define the absolute risk of type 1 diabetes.

    “For individuals who are positive for islet cell autoantibodies, HLA-DR/HLA-DQ genotyping will help define the absolute risk of type 1 diabetes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Early detection of albuminuria allows early intervention to reduce cardiovascular risk and delay overt diabetic nephropathy.

    “Early detection of albuminuria allows early intervention with the goal of reducing cardiovascular risk and delaying the onset of overt diabetic nephropathy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The ICA assay is labor-intensive and difficult to standardize, with marked interlaboratory variation in sensitivity and specificity demonstrated in workshops.

    “The ICA assay is labor-intensive and difficult to standardize, and marked interlaboratory variation in sensitivity and specificity has been demonstrated in workshops (284,314).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [284] Maclaren, 2001, Type 1 diabetes

      Not checked in the free run.

    • cites [314] Verge, 1998, Combined use of autoantibodies (IA-2 autoantibody, GAD autoantibody, insulin autoantibody, cytoplasmic islet cell antibodies) in type 1 diabetes: Combinatorial Islet Autoantibody Workshop, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The within-person variation in albumin excretion is large in people without diabetes and even higher in patients with diabetes.

    “The within-person variation in albumin excretion is large in people without diabetes and is even higher in patients with diabetes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [349] Howey, 1989, Biologic variation of urinary albumin: consequences for analysis, specimen collection, interpretation of results, and screening programs, Am J Kidney Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Recent data suggest that cardiovascular risk extends below the lower limit of 20 mg/min, reinforcing that albuminuria is a continuous variable for cardiovascular risk.

    “Recent data, however, suggest that risk extends below the lower limit of 20 mg/min (328-330), reinforcing the notion that this factor is a continuous variable for cardiovascular risk (331)(332)(333).”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [328] Klausen, 2006, Very low level of microalbuminuria is associated with increased risk of death in subjects with cardiovascular or cerebrovascular diseases, J Intern Med source

      Not checked in the free run.

    • cites [329] Klausen, 2005, New definition of microalbuminuria in hypertensive subjects: association with incident coronary heart disease and death, Hypertension source

      Not checked in the free run.

    • cites [330] Ratto, 2006, Microalbuminuria and cardiovascular risk assessment in primary hypertension: should threshold levels be revised?, Am J Hypertens source

      Not checked in the free run.

    • cites [331] Wachtell, 2003, Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: the LIFE study, Ann Intern Med source

      Not checked in the free run.

    • cites [332] Rachmani, 2000, Considerations about the threshold value of microalbuminuria in patients with diabetes mellitus: lessons from an 8-year follow-up study of 599 patients, Diabetes Res Clin Pract source

      Not checked in the free run.

    • cites [333] Pambianco, 2007, The prediction of major outcomes of type 1 diabetes: a 12-year prospective evaluation of three separate definitions of the metabolic syndrome and their components and estimated glucose disposal rate: the Pittsburgh Epidemiology of Diabetes Complications Study experience, Diabetes Care source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    At least some dipstick tests, especially as used in practice, have low sensitivity (high false-negative rates) and are unsuitable for screening; positive results must be confirmed by a laboratory method.

    “Thus, it appears that at least some of the tests, especially as used in practice, have the wrong characteristics for screening because of low sensitivity (high false-negative rates), and positive results must be confirmed by a laboratory method.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In healthy volunteers, the lowest within-person CVs were for albumin concentration in the first morning void (36%) and for the albumin-creatinine ratio in that sample (31%).

    “In healthy volunteers, the lowest within-person CVs were obtained for the concentration of albumin in the first morning void (36%) and for the albumin-creatinine ratio in that sample (31%) (349).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [349] Howey, 1989, Biologic variation of urinary albumin: consequences for analysis, specimen collection, interpretation of results, and screening programs, Am J Kidney Dis source

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    One dipstick was found to have >95% sensitivity.

    “One dipstick was found to have .95%sensitivity (322,324).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [322] Davidson, 2004, Peters Harmel A, Campese V, Basta E. ImmunoDip: an improved screening method for microalbuminuria, Am J Nephrol source

      Not checked in the free run.

    • cites [324] Sarafidis, 2008, A comparative evaluation of various methods for microalbuminuria screening, Am J Nephrol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    To keep analytical CV less than half the biological CV, an analytical goal of 18% CV has been proposed.

    “To keep the analytical CV less than half the biological CV, an analytical goal of an 18% CV has been proposed (349).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [349] Howey, 1989, Biologic variation of urinary albumin: consequences for analysis, specimen collection, interpretation of results, and screening programs, Am J Kidney Dis source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Diabetes is associated with a very high rate of cardiovascular events and is the leading cause of end-stage renal disease in the Western world.

    “Diabetes is associated with a very high rate of cardiovascular events and is the leading cause of end-stage renal disease in the Western world (321).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [321] ADA, 1999, Diabetes nephropathy, Diabetes Care

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most, but not all, methods agree well and support a reference interval of 2-20 mg albumin/mg creatinine.

    “Most, but not all, methods agree well and support a reference interval of 2-20 mg albumin/mg creatinine (348).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [348] Roberts, 1998, Comparison of four commercial urinary albumin (microalbumin) methods: implications for detecting diabetic nephropathy using random urine specimens, Clin Chim Acta source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    If a screening test has low sensitivity, negative results also must be confirmed, which is untenable.

    “If a screening test has low sensitivity, negative results also must be confirmed, a completely untenable approach.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationcitation

    The proposed strategies (specificity >99%, proficiency testing, multiple autoantibodies, sequential measurement) will reduce false-positive and false-negative results.

    “These strategies will reduce false-positive and false-negative results.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [279] Atkinson, 2001, Type 1 diabetes: new perspectives on disease pathogenesis and treatment, Lancet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The immunoassays for GAD65A and IA-2A are more reproducible and amenable to standardization than ICA.

    “The immunoassays are more reproducible and are amenable to standardization (309).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [309] Bingley, 2003, Diabetes Antibody Standardization Program: first assay proficiency evaluation, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neither centrifugation nor filtration appears necessary before storage at -20°C or -80°C.

    “Neither centrifugation nor filtration appears necessary before storage at 220°C or 280°C (359).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [359] MacNeil, 1991, Considerations when measuring urinary albumin: precision, substances that may interfere, and conditions for sample storage, Clin Chem source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    It is unclear whether assessing insulin resistance through insulin measurement has any advantage over assessment of physical signs of insulin resistance, and routine measurements of insulin are not recommended by the American College of Obstetrics and Gynecology.

    “It is unclear whether assessing insulin resistance through insulin measurement has any advantage over assessment of physical signs of insulin resistance (BMI, presence of acanthosis nigricans), and routine measurements of insulin are not recommended by the American College of Obstetrics and Gynecology (370).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [370] American College of Obstetrics and Gynecology, 2003, ACOG practice bulletin. Polycycstic ovary syndrome. Number 41, December 2002, Int J Gynaecol Obstet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Measures of insulin resistance (including insulin measurements) predict the risk of diabetes or coronary artery disease only moderately well, with no threshold effects.

    “More-recent analyses suggest that insulin values do not add significantly to diabetes risk prediction carried out with more traditional clinical and laboratory measurements (366) and that measures of insulin resistance (that include insulin measurements) predict the risk of diabetes or coronary artery disease only moderately well, with no threshold effects (367).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [367] Rutter, 2008, Use of alternative thresholds defining insulin resistance to predict incident type 2 diabetes mellitus and cardiovascular disease, Circulation source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An increased insulin concentration is a surrogate marker that can be used to estimate resistance to insulin-mediated glucose disposal and identify individuals at risk for developing syndrome X.

    “An increased insulin concentration is a surrogate marker that can be used to estimate resistance to insulinmediated glucose disposal, and it can identify individuals at risk for developing syndrome X, also known as the insulin resistance syndrome or the metabolic syndrome (363).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [363] Reaven, 1996, Insulin resistance and its consequences; non-insulin dependent diabetes mellitus and coronary heart disease

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Because of the critical role of insulin resistance in the pathogenesis of type 2 diabetes, hyperinsulinemia would appear to be a logical risk predictor for incident type 2 diabetes.

    “Because of the critical role of insulin resistance in the pathogenesis of type 2 diabetes, hyperinsulinemia would also appear to be a logical risk predictor for incident type 2 diabetes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The Insulin Standardization Workgroup called for harmonization of the insulin assay to encourage development of practical measures of insulin sensitivity and secretion for clinical care.

    “The Insulin Standardization Workgroup called for harmonization of the insulin assay to encourage the development of measures of insulin sensitivity and secretion that will be practical for clinical care (374).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [374] Staten, 2010, Insulin assay standardization: leading to measures of insulin sensitivity and secretion for practical clinical care, Diabetes Care source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The urinary albumin excretion rate does not show marked diurnal variation in diabetes but does so in essential hypertension.

    “The urinary albumin excretion rate does not show marked diurnal variation in diabetes but does so in essential hypertension (360).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [360] Hishiki, 1998, Circadian variation of urinary microalbumin excretion and ambulatory blood pressure in patients with essential hypertension, J Hypertens source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Whether urine is centrifuged, filtered, or untreated, albumin concentration decreases by 0.27%/day at -20°C but shows no decrease over 160 days at -80°C.

    “Whether a urine sample is centrifuged, filtered, or not treated, the albumin concentration decreases by 0.27%/day at 220°C but shows no decreases over 160 days at 280°C (359).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [359] MacNeil, 1991, Considerations when measuring urinary albumin: precision, substances that may interfere, and conditions for sample storage, Clin Chem source

      Not checked in the free run.

175 of 175

  • The paper relies on this without support.

    The quality of scientific evidence supporting laboratory tests for diabetes varies substantially.

    “The quality of the scientific evidence supporting the use of these tests varies substantially.”

  • The paper relies on this without support.

    Hypoglycemia is a major, potentially life-threatening complication of diabetes treatment.

    “Hypoglycemia is a major, potentially life-threatening complication of the treatment of diabetes.”

  • The paper relies on this without support.

    Most glucose meters are inaccurate at very high or very low glucose concentrations.

    “most meters are inaccurate at very high or very low glucose concentrations.”

  • The paper relies on this without support.

    The concentration of glucose in interstitial fluid correlates with blood glucose.

    “The underlying fundamental concept is that the concentration of glucose in the interstitial fluid correlates with blood glucose.”

  • The paper relies on this without support.

    Urine glucose provides no information about blood glucose concentrations below the variable renal glucose threshold of approximately 10 mmol/L.

    “Although urine glucose is detectable in patients with grossly increased blood glucose concentrations, it provides no information about blood glucose concentrations below the variable renal glucose threshold [approximately 10 mmol/L (180 mg/dL)].”

  • The paper relies on this without support.

    Semiquantitative urine glucose tests cannot distinguish between euglycemia and hypoglycemia.

    “Semiquantitative urine glucose tests also cannot distinguish between euglycemia and hypoglycemia.”

  • The paper relies on this without support.

    The extent to which the kidney concentrates urine affects urine glucose concentrations, and only mean glucose values between voidings are reflected.

    “Furthermore, the extent to which the kidney concentrates the urine will affect urine glucose concentrations, and only mean glucose values between voidings are reflected.”

  • The paper relies on this without support.

    Test methods that detect reducing substances are subject to numerous interferences, including many drugs and nonglucose sugars.

    “Test methods that detect reducing substances are not recommended because they are subject to numerous interferences, including numerous drugs and nonglucose sugars.”

  • The paper relies on this without support.

    The ketone bodies acetoacetate, acetone, and beta-hydroxybutyric acid are catabolic products of free fatty acids.

    “The ketone bodies acetoacetate (AcAc), acetone, and b-hydroxybutyric acid (bHBA) are catabolic products of free fatty acids.”

  • The paper relies on this without support.

    Ketone bodies are usually present in urine and blood at very low concentrations, such as total serum ketones below 0.5 mmol/L.

    “Ketone bodies are usually present in urine and blood, but in very low concentrations (e.g., total serum ketones, ,0.5 mmol/L).”

  • The paper relies on this without support.

    The principal ketone bodies beta-hydroxybutyrate and acetoacetate are typically present in approximately equimolar amounts.

    “The principal ketone bodies bHBA and AcAc are typically present in approximately equimolar amounts.”

  • The paper relies on this without support.

    Acetone is derived from spontaneous decarboxylation of acetoacetate.

    “Acetone, usually present in only small quantities, is derived from spontaneous decarboxylation of AcAc.”

  • The paper relies on this without support.

    Urine ketone concentrations in healthy individuals are below the detection limits of commercially available testing materials.

    “The concentrations of ketones in the urine of healthy individuals are below the detection limits of commercially available testing materials.”

  • The paper relies on this without support.

    False-negative urine ketone readings have been reported with highly acidic urine, such as after large intakes of ascorbic acid.

    “False-negative readings have also been reported with highly acidic urine samples, such as after large intakes of ascorbic acid.”

  • The paper relies on this without support.

    Loss of ketones from urine due to microbial action can cause false-negative readings.

    “Loss of ketones from urine attributable to microbial action can also cause false-negative readings.”

  • The paper relies on this without support.

    Acetone is a highly volatile substance.

    “Because acetone is a highly volatile substance, samples should be kept in a closed container.”

  • The paper relies on this without support.

    The nitroprusside-containing reagent is much more sensitive to acetoacetate than to acetone with respect to color generation.

    “The nitroprusside-containing reagent is much more sensitive to AcAc than acetone with respect to color generation.”

  • The paper relies on this without support.

    Ascorbic acid interferes with some blood ketone assay methods.

    “Ascorbic acid interferes with some assay methods.”

  • The paper relies on this without support.

    Acetoacetate interferes with some blood ketone assay methods unless the samples are highly dilute.

    “AcAc interferes with some assay methods unless the samples are highly dilute.”

  • The paper relies on this without support.

    Enzymatic beta-hydroxybutyrate methods use beta-hydroxybutyrate dehydrogenase with NAD+ to convert beta-hydroxybutyrate to acetoacetate and NADH.

    “The principle of the enzymatic methods is that b-hydroxybutyrate dehydrogenase in the presence of NAD 1 converts bHBA to AcAc and NADH.”

  • The paper relies on this without support.

    The NADH produced can be quantified spectrophotometrically, usually kinetically, with a peroxidase reagent.

    “The NADH produced can be quantified spectrophotometrically (usually kinetically) with the use of a peroxidase reagent.”

  • The paper relies on this without support.

    Most beta-hydroxybutyrate methods permit the use of whole-blood, plasma, or serum samples.

    “Most methods permit the use of wholeblood, plasma, or serum samples (required volumes are generally #200 mL).”

  • The paper relies on this without support.

    Several beta-hydroxybutyrate methods are available as handheld meters that have been FDA cleared for both laboratory and home use by patients.

    “Several methods are available as handheld meters, which have been FDA cleared for both laboratory use and home use by patients.”

  • The paper relies on this without support.

    Patients with alcoholic ketoacidosis have positive urine ketone readings, but hyperglycemia is not usually present.

    “Patients with alcoholic ketoacidosis will have positive urine ketone readings, but hyperglycemia is not usually present.”

  • The paper relies on this without support.

    Reference intervals for beta-hydroxybutyrate differ among assay methods, but concentrations in healthy individuals who have fasted overnight are generally below 0.5 mmol/L.

    “Reference intervals for bHBA differ among assay methods, but concentrations in healthy individuals who have fasted overnight are generally ,0.5 mmol/L.”

  • The paper relies on this without support.

    Patients with well-documented diabetic ketoacidosis generally have beta-hydroxybutyrate concentrations above 2 mmol/L.

    “Patients with well-documented DKA [serum CO 2 ,17 mmol/L, arterial pH ,7.3, plasma glucose .14.9 mmol/L (250 mg/dL)] generally have bHBA concentrations .2mmol/L.”

  • The paper relies on this without support.

    Food intake has no significant effect on HbA1c test results.

    “Food intake has no significant effect on test results.”

  • The paper relies on this without support.

    Boronate affinity chromatography assay methods are generally considered less affected by hemoglobin variants than other methods.

    “Boronate affinity chromatography assay methods are generally considered to be less affected by Hb variants than other methods.”

  • The paper relies on this without support.

    Improper sample handling, such as storage at high temperatures, can introduce large artifacts that may not be detectable depending on the assay method.

    “Improper handling of samples, such as storage at high temperatures, can introduce large artifacts that may not be detectable, depending on the assay method.”

  • The paper relies on this without support.

    Frozen whole-blood controls stored in single-use aliquots at -70°C or colder are ideal and are stable for months or even years, depending on the assay method.

    “Frozen whole-blood controls stored in single-use aliquots at 270°C or colder are ideal and are stable for months or even years, depending on the assay method.”

  • The paper relies on this without support.

    Lyophilized controls are commercially available but may show matrix effects when new reagents or columns are introduced, depending on the assay method.

    “Lyophilized controls are commercially available but, depending on the assay method, may show matrix effects when new reagents or columns are introduced.”

  • The paper relies on this without support.

    Most currently available automated assays either remove labile pre-HbA1c during the assay or do not measure the labile product.

    “Most currently available automated assays either remove the labile pre-HbA 1c during the assay process or do not measure the labile product.”

  • The paper relies on this without support.

    Each 1% change in HbA1c relates to a change in mean plasma glucose of approximately 1.6 mmol/L (29 mg/dL).

    “For example, each 1% (approximately 11 mmol/mol) change in HbA 1c is related to a change in the mean plasma glucose concentration of approximately 1.6 mmol/L (29 mg/dL).”

  • The paper relies on this without support.

    HbA1c measurements are now a routine component of clinical management of patients with diabetes.

    “HbA 1c measurements are now a routine component of the clinical management of patients with diabetes.”

  • The paper relies on this without support.

    There is no consensus on the optimal frequency of HbA1c testing.

    “There is no consensus on the optimal frequency of HbA 1c testing.”

  • The paper relies on this without support.

    The frequency of HbA1c testing for diagnosis has not been established.

    “The frequency of HbA 1c testing for diagnosis has not been established, but guidelines similar to those for glucose-based testing seem appropriate.”

  • The paper relies on this without support.

    The binding of labeled autoantigen to autoantibodies is normally distributed.

    “The binding of labeled autoantigen to autoantibodies is normally distributed.”

  • The paper relies on this without support.

    Increases over time to macroalbuminuria (>300 mg/day) are associated with kidney disease and increased risk for progression to end-stage renal disease.

    “Albuminuria (formerly microalbuminuria) are a well-established cardiovascular risk marker, in which increases over time to macroalbuminuria (.300 mg/day) are associated with kidney disease and an increased risk for progression to endstage renal disease.”

  • The paper relies on this without support.

    Conventional qualitative tests (dipsticks) for albuminuria do not detect small increases in urinary albumin excretion.

    “Conventional qualitative tests (chemical strips or “dipsticks”) for albuminuria do not detect the small increases of urinary albumin excretion.”

  • The paper relies on this without support.

    Chemical-strip methods are not sensitive when urine albumin concentration is 20-50 mg/L.

    “Chemical-strip methods are not sensitive when the albumin concentration in the urine is in the interval of 20-50 mg/L.”

  • The paper relies on this without support.

    The diagnosis of an islet cell tumor is based on persistence of inappropriately increased plasma insulin concentrations in the face of low glucose.

    “The diagnosis of an islet cell tumor is based on the persistence of inappropriately increased plasma insulin concentrations in the face of a low glucose concentration.”

  • The paper relies on this without support.

    An increase in the ratio of fasting proinsulin to insulin in patients with hypoglycemia strongly suggests the presence of an islet cell tumor.

    “In addition, an increase in the ratio of fasting proinsulin to insulin in patients with hypoglycemia strongly suggests the presence of an islet cell tumor.”

  • The paper relies on this without support.

    Women with polycystic ovary syndrome manifest insulin resistance by androgen excess and abnormalities of carbohydrate metabolism; both may respond to metformin or thiazolidinediones.

    “Women with this syndrome manifest insulin resistance by androgen excess, as well as by abnormalities of carbohydrate metabolism; both abnormalities may respond to treatment with metformin or thiazolidinediones.”

  • The paper relies on this without support.

    Proinsulin reference intervals are dependent on methodology, and each laboratory should establish its own reference interval.

    “Proinsulin reference intervals are dependent on methodology, and each laboratory should establish its own reference interval.”

  • The paper relies on this without support.

    In the case of C-peptide, there is a discrepancy in reliability because of variable specificity among antisera, lack of standardization of C-peptide calibration, and variable crossreactivity with proinsulin.

    “In the case of Cpeptide, there is a discrepancy in reliability because of variable specificity among antisera, lack of standardization of Cpeptide calibration, and variable crossreactivity with proinsulin.”

  • The paper relies on this without support.

    The U.S. Centers for Medicare and Medicaid Services requires Medicare patients to have C-peptide measured to be eligible for coverage of insulin pumps.

    “Of note is the requirement of the U.S. Centers for Medicare and Medicaid Services that Medicare patients have C-peptide measured in order to be eligible for coverage of insulin pumps.”

  • The paper relies on this without support.

    In the vast majority of patients, the titer of insulin antibodies is low, and their presence is of no clinical significance.

    “In the vast majority of patients, the titer of insulin antibodies is low, and their presence is of no clinical significance.”

  • The paper relies on this without support.

    On occasion, the titer of insulin antibodies can be quite high and associated with dramatic resistance to exogenous insulin's glucose-lowering effect.

    “On occasion, however, the titer of insulin antibodies in the circulation can be quite high and associated with a dramatic resistance to the ability of exogenous insulin to lower plasma glucose concentrations.”

  • The paper relies on this without support.

    This clinical situation is quite rare, usually occurs in insulin-treated patients with type 2 diabetes, and the cause-and-effect relationships between insulin antibody magnitude and insulin resistance are unclear.

    “This clinical situation is quite rare, it usually occurs in insulin-treated patients with type 2 diabetes, and the cause-and-effect relationships between the magnitude of the increase in insulin antibodies and the degree of insulin resistance are unclear.”

  • The paper relies on this without support.

    A quantitative estimate of circulating insulin antibodies does not appear to be of significant benefit.

    “There are several therapeutic approaches for treating these patients, and a quantitative estimate of the concentration of circulating insulin antibodies does not appear to be of significant benefit.”

  • The paper relies on this without support.

    The evidence accumulated in the last 7 to 8 years has failed to identify any clinical value in measuring amylin and leptin in patients with diabetes.

    “The evidence that has accumulated in the last 7 to 8 years has failed to identify any clinical value in measuring these analytes in patients with diabetes.”

  • The paper relies on this without support.

    GAD65A may be present in approximately 60%-80% of patients with newly diagnosed type 1 diabetes, with frequency varying by sex and age.

    “GAD65A may be present in approximately 60%-80% of patients with newly diagnosed type 1 diabetes, but the frequency varies with sex and age.”

  • The paper relies on this without support.

    IA-2As may be present in 40%-50% of patients with newly diagnosed type 1 diabetes, with frequency highest in the young and decreasing with age.

    “IA-2As may be present in 40%-50% of patients with newly diagnosed type 1 diabetes, but the frequency is highest in the young.The frequency decreases with increasing age.”

  • The paper relies on this without support.

    IAA positivity occurs in 70%-80% of children who develop type 1 diabetes before 5 years of age but in <40% of individuals who develop diabetes after age 12.

    “IAA positivity occurs in .70%-80% of children who develop type 1 diabetes before 5 years of age but occurs in ,40% of individuals who develop diabetes after the age of 12 years.”

  • The paper relies on this without support.

    ICA is found in about 75%-85% of new-onset patients.

    “ICA is found in about 75%-85% of new-onset patients.”

  • The paper relies on this without support.

    In 80% of patients with type 1 diabetes and low levels of albuminuria, urinary albumin excretion can increase by as much as 10%-20%/year, with development of clinical proteinuria in 10-15 years in more than half.

    “In 80% of patients with type 1 diabetes and low levels of albuminuria, urinary albumin excretion can increase by as much as 10%-20%/year, with the development of clinical proteinuria (.300 mg albumin/day) in 10-15 years in more than half the patients.”

  • The paper relies on this without support.

    After clinical-grade proteinuria occurs, >90% of patients develop decreased GFR and ultimately end-stage renal disease.

    “After clinical-grade proteinuria occurs, .90% of patients develop a decreased GFR and, ultimately, end-stage renal disease.”

  • The paper relies on this without support.

    In type 2 diabetes, 20%-40% of patients with stage A2 albuminuria progress to overt nephropathy, but by 20 years after overt nephropathy, approximately 20% develop end-stage renal disease.

    “In type 2 diabetes, 20%-40% of patients with stage A2 albuminuria (Table 8) progress to overt nephropathy, but by 20 years after overt nephropathy, approximately 20% develop end-stage renal disease.”

  • The paper relies on this without support.

    Patients with diabetes (type 1 or type 2) and stage A2 albuminuria are at increased risk for cardiovascular disease.

    “In addition, patients with diabetes (type 1 or type 2) and stage A2 albuminuria are at increased risk for cardiovascular disease.”

  • The paper relies on this without support.

    Albuminuria (stage A2) rarely occurs with a short duration of type 1 diabetes or before puberty.

    “Albuminuria (stage A2) rarely occurs with a short duration of type 1 diabetes or before puberty.”

  • The paper relies on this without support.

    Older patients (age >75 years or life expectancy <20 years) may not be at risk for clinically significant nephropathy because of short projected life span, but they will be at higher cardiovascular risk.

    “Although older patients (age .75 years or a life expectancy ,20 years) may not be at risk for clinically significant nephropathy because of a short projected life span, they will be at higher cardiovascular risk.”

  • The paper relies on this without support.

    Collection of 24-h samples has disadvantages because many samples are collected inadequately and total creatinine is not routinely checked to evaluate adequacy.

    “Collection of 24-h samples has disadvantages, specifically because many samples are collected inadequately and because total creatinine is not routinely checked to evaluate the adequacy of collection.”

  • The paper relies on this without support.

    Although the albumin-creatinine ratio appears acceptable for screening, limited data are available on its use in monitoring response to therapy.

    “Although the ratio appears entirely acceptable for screening, limited data are available on its use in monitoring the response to therapy.”

  • The paper relies on this without support.

    Earlier studies may not have controlled well for glycemic status and other confounders.

    “Earlier studies may not have controlled well for glycemic status and other confounders.”

  • The paper relies on this without support.

    The optimal laboratory evaluation of polycystic ovary syndrome patients in routine clinical care has not been clearly defined.

    “Although clinical trials have generally evaluated insulin resistance by using the hyperinsulinemic euglycemic clamp, ratios of fasting glucose to insulin, and other modalities, the optimal laboratory evaluation of these patients in routine clinical care has not been clearly defined.”

  • The paper relies on this without support.

    A committee has been established under the auspices of the CDC to harmonize C-peptide analysis.

    “A committee has been established under the auspices of the CDC to harmonize C-peptide analysis.”

  • The paper relies on this without support.

    There are several therapeutic approaches for treating patients with high insulin antibody titers, and a quantitative estimate of circulating insulin antibodies does not appear to be of significant benefit.

    “There are several therapeutic approaches for treating these patients, and a quantitative estimate of the concentration of circulating insulin antibodies does not appear to be of significant benefit.”
67 of 67

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Using a single elevated oral glucose tolerance test value is justified because each of the three values independently predicts adverse pregnancy outcomes and because laboratory precision and accuracy have improved since the 1960s.

    “This use of a single elevated value is justified by the finding that each of the 3 OGTT values is independently predictive of adverse pregnancy outcomes 16 and the fact that laboratory precision and accuracy are much improved now 20 compared with the 1960s when O'Sullivan and Mahan 7 required 2 elevated values to guard against errors.”

    From One-step or 2-step testing for gestational diabetes: which is better? (2021) · cites this paper as [20]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • A 7% HbA1c result has two different unit equivalents

    Minor

    The example labels 7% HbA1c as 42 mmol/mol, while elsewhere the paper labels 7% as 53 mmol/mol.

  • Urine albumin cutoffs use conflicting creatinine units

    Minor

    The definition gives the albumin-to-creatinine cutoff in mg/mg, while the subsequent interpretation uses the same numerical cutoff in mg/g. Those units differ by a factor of 1,000.

  • Participant percentage does not match the count

    Minor

    Twenty-two of 31 participants is approximately 71%, not 77%.

    Reported 77 · recomputed 70.967742

  • The second glucose interval also exceeds its stated percentage

    Minor

    A range of 5.6 mmol/L ± 6.4% is approximately 5.24-5.96 mmol/L, not 4.9-6.3 mmol/L.

  • The stated glucose interval exceeds its stated percentage

    Minor

    A range of 7.0 mmol/L ± 6.4% is approximately 6.55-7.45 mmol/L, not 6.1-7.9 mmol/L.

5 of 5

The citation lists haven’t been fetched yet

References 398 · Cited by 718

Research works printed but not linked: 15

  1. IDF, 2008, Diabetes Atlas
  2. IDF, 2005, Task Force. Global guideline for type 2 diabetes
  3. Ladenson, 1980, Nonanalytical sources of variation in clinical chemistry results
  4. Sacks, 2006, Carbohydrates
  5. ADA, 1987, Consensus statement on self-monitoring of blood glucose, Diabetes Care, 10, 93
  6. NCCLS, 1994, Ancillary (bedside) blood glucose testing in acute and chronic care facilities; approved guideline C30-A, Villanova (PA): NCCLS, 14, 1
  7. D'arrigo, 1999, Beyond blood glucose, Diabetes Forecast, 52, 37
  8. ADA, 2000, Provider Notes: the newsletter of the ADA/NCQA Provider Recognition Program, Provid Notes, 1, 1
  9. Goldstein, 1997, Bringing order to chaos: the National Glycohemoglobin Standardization Program, Contemp Int Med, 9, 27
  10. Little, 1998, A simple blood collection device for analysis of glycohemoglobin (GHB), Clin Chem, 44, A139
  11. Sacks, 2010, CAP surveys: participant summary for glycohemoglobin survey 2010 set GH2-A, Northfield, IL
  12. Redondo, 2000, DR- and DQ-associated protection from type 1A diabetes: comparison of DRB1*1401 and DQA1*0102-DQB1*0602*, J Clin Endocrinol Metab, 85, 3793
  13. Maclaren, 2001, Type 1 diabetes
  14. ADA, 1999, Diabetes nephropathy, Diabetes Care, 22, S66
  15. Reaven, 1996, Insulin resistance and its consequences; non-insulin dependent diabetes mellitus and coronary heart disease

Authors
Sacks, D. B., Arnold, M., Bakris, G. L., Bruns, D. E., Horvath, A. R., Kirkman, M. S., Lernmark, A., Metzger, B. E., & Nathan, D. M.
Affiliations
  • National Institutes of Health (US)
  • University of Iowa (US)
  • University of Chicago (US)
  • University of Virginia Medical Center (US)
  • The University of Sydney (AU)
  • American Diabetes Association (US)
  • Department of Clinical Sciences, Lund University/CRC, Skane University Hospital Malmö, Malmö, Sweden; the
  • Northwestern University (US)
  • Harvard University (US)
Corresponding author
Sacks, David B.
ORCID
Venue
Diabetes Care
Publisher
American Diabetes Association
Published
2011-05-20
Volume
34
Issue
6
Pages
e61-e99
ISSN
  • 0149-5992 (ISSN-L)
  • 1935-5548
DOI
10.2337/dc11-9998
PMC
PMC3114322
OpenAlex
W2022757173
Cited by
718
References
398
Citations by year
2026: 5 · 2025: 23 · 2024: 26 · 2023: 36 · 2022: 33 · 2021: 38 · 2020: 41 · 2019: 58 · 2018: 58 · 2017: 53 · 2016: 57 · 2015: 74 · 2014: 68 · 2013: 39 · 2012: 31
FWCI
39.57
Type
journal article
Language
en
Open access
Locations
  • Diabetes Care (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • Lund University Publications (Lund University) (submittedVersion)
Funders
  • Walgreens
  • GlaxoSmithKline
  • PepsiCo
  • Partnership for Clean Competition
  • National Institutes of Health
  • Abbott Diagnostics
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Physiology › Clinical Laboratory Practices and Quality Control
Keywords
diabetes mellitus, laboratory testing, diabetes diagnosis, glycemic control monitoring, HbA1c, self-monitoring of blood glucose, non-invasive glucose monitoring, genetic testing, autoantibodies, urinary albumin, insulin, proinsulin, C-peptide, evidence quality grading, clinical guidelines
MeSH terms
Blood Glucose, Diabetes Mellitus, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Glycated Hemoglobin, Humans, Clinical Laboratory Techniques

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-04.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-04.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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