CAM 20494

Genetic Testing for Lactase Insufficiency

Category:Laboratory   Last Reviewed:July 2018
Department(s):Medical Affairs   Next Review:July 2019
Original Date:June 2013    

Description
Genetic testing of adults with suspected lactase insufficiency is proposed as an alternative to current diagnostic practices, which include hydrogen breath test (HBT), lactose tolerance blood test (LTT) and intestinal biopsy.

Studies have demonstrated a high correlation between a single nucleotide polymorphism (SNP), -13910 C>T upstream of the gene encoding the enzyme lactase, and lactase insufficiency in persons of European ancestry. Studies in white populations report a high degree of agreement for the diagnosis of lactase insufficiency between genotyping and both HBT and LTT.

Genetic testing has the potential advantage of sparing patients the discomfort of fasting and experiencing symptoms of lactose intolerance during the administration of HBT or LTT. Genotyping also may have additional utility in the diagnosis of secondary hypolactasia.

However, there is no current treatment for lactase insufficiency, and management involves dietary restriction and palliation of lactose intolerance symptoms. Therefore, an empiric diagnosis of lactose intolerance in the absence of confirmation by HBT, LTT or genotyping, followed by treatment with dietary restriction of lactose, is suitable. Currently there is insufficient evidence that the assessment of the genetic etiology of lactose intolerance would affect patient management or improve clinical outcomes. The use of targeted mutation analysis of -13910 C>T for the prediction of lactase insufficiency is, therefore, considered investigational.

Background
The predominant carbohydrate in milk is the disaccharide lactose, comprising the simple sugars glucose and galactose. The brush-border enzyme, lactase (also called lactase-phlorizin hydrolase), hydrolyzes lactose into its monosaccharide components, which are absorbable by the intestinal mucosa. Except for rare instances of congenital hypolactasia, most infants are able to produce lactase, and enzyme levels are highest at birth. Sometime after weaning in most children, there is a decrease in lactase production through a multifactorial process that is regulated at the gene transcription level.1 

The decrease in lactase level varies significantly by ethnic group both in terms of the lowest level of lactase and time from weaning necessary to reach the nadir of lactase activity.2 By 2 to 12 years of age, two groups emerge: a group with insufficient levels of lactase activity (primary hypolactasia or lactase nonpersistence) and a group that retains the infant level of lactase activity through adulthood (lactase-persistence).3 Ethnic groups with the highest prevalences of lactase insufficiency are Asian, Native American and blacks, with the lowest prevalences in people of northern European origin (see Table 1).

Table 1. Prevalence of Lactase Insufficiency by Country or Ethnicity4

Population 

Lactase Insufficiencyª 

Northern Europeans   2 to 15  
American Whites   6 to 22  
Central Europeans   9 to 23  
Northern Indians   20 to 30  
Southern Indians   60 to 70  
Hispanics   50 to 80  
Ashkenazi Jews   60 to 80  
Blacks   60 to 80  
American Indians   80 to 100  
Asians   95 to 100  

a Identified through hydrogen breath test (HBT) or lactose tolerance blood test (LTT). 

Several terms are used to describe lactose malabsorption:

  • Lactase insufficiency (lactase nonpersistence or primary hypolactasia) indicates that lactase activity is a fraction of the original infantile level. Direct measurement of lactase activity is tested biochemically through duodenal biopsy.5 Lactase insufficiency is highly correlated with the C/C genotype at -13910 in the lactase promoter region. In adults homozygous for the lactase persistence genotype (T/T), lactase levels are approximately 10 times higher than in those who are homozygous lactase insufficient (C/C). Heterozygous persons (C/T) have intermediate lactase activity levels.6 In heterozygous people, symptoms of lactose intolerance may appear if the quantity of ingested lactose exceeds the maximum digestible by the reduced level of lactase.
  • Lactose malabsorption indicates that a large portion of lactose cannot be absorbed in the small bowel and is delivered to the colon. Malabsorption is tested by HBT or LTT.5 
  • Lactose intolerance indicates that lactose malabsorption causes gastrointestinal symptoms. There is no genetic test for lactose intolerance. Demonstration of lactose intolerance requires patients to self-report symptoms (listed in Table 2) after lactose ingestion. Diagnosis of lactose intolerance is highly susceptible to the placebo effect, and studies should conduct a blinded lactose challenge with an indistinguishable placebo.3  A 2010 meta-analysis by Jellema et al. indicated that no specific patient complaint could predict lactose malabsorption. For common lactose intolerance symptoms, sensitivity and specificity ranged from 0 percent to 90 percent and 18 percent to 96 percent, respectively.7 Similarly, patient self-reported milk intolerance was inaccurate for predicting lactose malabsorption, with sensitivity and specificity ranging from 30 percent to 70 percent and 25 percent to 87 percent, respectively.7

Table 2. Symptoms of Lactose Intolerance2

Symptoms

Percent of Total Patients Who Experience Symptom 

Gut-related symptoms  

 
Abdominal pain   100  
Gut distention   100  
Borborygmi (stomach rumbling)  100  
Flatulence   100  
Diarrhea   70  
Nausea 78 
Vomiting 78  
Constipation 30  

Systemic symptoms 

 
Headache and light headedness   86  
Loss of concentration and poor short-term memory   82  
Muscle pain   71  
Joint pain and/or swelling   71  
Long-term fatigue  63 
Allergy (eczema, pruritus, rhinitis, sinusitis, asthma)   40  
Mouth ulcers   30 
Heart arrhythmia   24  
Increased frequency of micturition   <20  
Sore throat   <20  

Lactase insufficiency is common, occurring in approximately 70 percent of persons after weaning.8 Lactase insufficiency results in lactose malabsorption, which may lead to symptoms of lactose intolerance, such as abdominal pain, bloating, diarrhea and increased flatulence, caused by bacterial fermentation of undigested lactose in the colon.9 However, the demonstration of lactose malabsorption does not necessarily indicate that a person will be symptomatic. Factors that determine whether a person with lactose malabsorption will develop symptoms include the dose of lactose ingested; residual intestinal lactase activity; ingestion of food along with lactose; ability of the colonic flora to ferment lactose; and individual sensitivity to the products of lactose fermentation. Because of these factors, the number of persons reporting symptoms of lactose intolerance is likely only a portion of those who are lactase insufficient. In addition, lactose malabsorption may be secondary (secondary hypolactasia) to acquired conditions, such as small bowel bacterial overgrowth; infectious enteritis; mucosal damage due to celiac disease; inflammatory bowel disease; antibiotics; gastrointestinal surgery; short bowel syndrome; radiation enteritis; or other conditions that may lead to reduced lactase expression in the small intestine.6 

Clinical Diagnosis of Lactase Insufficiency
Mucosal biopsy of the duodenum followed by biochemical lactase assay to directly measure lactase activity is the criterion standard for diagnosing lactase insufficiency. Although this approach also may exclude other causes of secondary lactose malabsorption, utility is limited due to the invasiveness of the procedure and the patchy expression of lactase in the duodenum.

Two common alternatives to this direct method of measuring lactase activity are the HBT and LTT, which measure lactose malabsorption. Because lactose malabsorption is nearly always attributable to lactase insufficiency, this typically can be imputed from assessment of lactose malabsorption.3 

The HBT measures by gas chromatography the amount of hydrogen exhaled for up to three hours after ingesting 25 to 50 g of lactose. Persons undergoing HBT are required to fast overnight and refrain from activities that may elevate breath hydrogen during testing. A rise in breath hydrogen of 0.31 to 2.5 mL/min is indicative of bacterial fermentation from malabsorbed lactose. A negative HBT can exclude lactose malabsorption as the cause of symptoms, and a positive result indicates that symptoms may be attributable to lactose ingestion.3 The following factors are associated with increased breath hydrogen and may cause false-positive results if present at the time of testing:

  • Diabetes
  • Small bowel disease (e.g., celiac, giardiasis)
  • Bacterial overgrowth
  • Altered colon pH
  • Antibiotic usage
  • Probiotic usage
  • Smoking
  • Exercise
  • Aspirin usage
  • Colonic bacterial adaptation

The LTT measures blood glucose increase over time with blood drawn at 15, 30, 60 and 90 minutes after ingesting a 25- to 50-g dose of lactose. A glucose increase of less than 20 mg/dL above an eight-hour fasting level indicates an abnormal test. The following factors are associated with a rise in blood sugar when undergoing a lactose tolerance test and may cause false-positive results:

  • Diabetes
  • Small-bowel disease (e.g., celiac, giardiasis)
  • Thyroid disorders
  • Motility disorders (stomach, small bowel)
  • Bacterial overgrowth

Molecular Diagnosis of Lactase Insufficiency

In 2002, Enattah et al. identified the first DNA variant to control transcription of lactase.10  This polymorphism, -13910 C>T, is located in a noncoding region of the MCM6 gene that is upstream of the lactase gene (LCT). The less common T allele has been associated with lactase persistence and has demonstrated an autosomal dominant pattern of inheritance. This polymorphism is thought to be related to the domestication of animals during the last 10,000 to 12,000 years, and persons with the C/C genotype have been shown to be strongly associated with a lactase insufficiency phenotype in whites. Other polymorphisms in the same MCM6 regulatory region are associated with other ethnic groups (e.g., Africans, Arabs), but the prevalences of these vary geographically6,11 and, to date, no commercially available testing kits have incorporated these polymorphisms. 

Prometheus’s LactoTYPE® is a commercially available polymerase chain reaction‒based test that assesses the most common lactase nonpersistence variant, MCM6-13910 C>T, in patients with suspected lactose intolerance. Fulgent Clinical Diagnostics Lab also offers MCM6 sequencing and deletion/duplication analysis using next-generation sequencing. Demonstration of the C/C genotype can be used as indirect evidence of lactase insufficiency and lactose malabsorption. 

Treatment of Lactase Insufficiency
The goal of treatment should be to ensure adequate nutrition for skeletal health.1 For patients with lactase insufficiency, dietary adjustment to restrict the consumption of foods containing lactose is the principal form of therapy. However, even lactose maldigesters can usually tolerate small amounts of lactose (12 g/d) with no or minimal symptoms. Lactase enzyme preparations are available for symptom relief, but may not be effective in all patients.

Regulatory Status
No U.S. Food and Drug Administration‒cleared genotyping tests were found. Thus, genotyping is offered as a laboratory-developed test. Clinical laboratories may develop and validate tests in-house (“homebrew”) and market them as a laboratory service. Such tests must meet general regulatory standards of the Clinical Laboratory Improvement Act (CLIA).The laboratory offering the service must be licensed by CLIA for high-complexity testing.

Policy
The use of targeted mutation analysis of -13910 C>T for the prediction of lactase insufficiency is considered INVESTIGATIONAL.

Policy Guidelines
Effective July 1, 2013, the following test will be included under CPT code 81400:

LCT (lactase-phlorizin hydrolase) (e.g., lactose intolerance), 13910 C>T variant

Rationale
This policy was created in 2013 and is based on a search of the MEDLINE database through March 10, 2015 (see Appendix Table 1 for genetic testing categories). Literature describing the analytic validity, clinical validity and clinical utility of genetic testing for lactase insufficiency was sought.

Analytic Validity
Analytic validity is the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent. According to the Genetic Testing Registry, analytical sensitivity of next-generation sequencing and deletion/duplication analysis of MCM6 exceeds 98 percent. Analytical specificity and accuracy are 96 percent and 97 percent, respectively.12 

Clinical Validity
Clinical validity is the diagnostic performance of the test (sensitivity, specificity, positive and negative predictive values) in detecting clinical disease.

Many reports on the diagnosis of lactase insufficiency by polymerase chain reaction (PCR) mutation analysis of -13910 C>T have been published, and those that assess the agreement between genotyping and hydrogen breath test (HBT), lactose tolerance blood test (LTT) or biopsy are presented in Table 3. Nineteen studies compared genotyping of single nucleotide polymorphism (SNP) -13910 C>T to HBT and found sensitivities and specificities ranging from 71 percent to 100 percent and 46 percent to 100 percent, respectively. Five studies compared genotyping with LTT with sensitivities and specificities ranging from 85 percent to 100 percent and 87 percent to 95 percent, respectively. One study compared genotyping to a hydrogen/methane breath test, which may be more sensitive than HBT, and reported Cohen’s kappa statistic (κ) of 0.44, indicating moderate agreement.13 Heterogeneity in study populations, dose of lactose given in HBT/LTT and age of participants contributed to the wide range of observed sensitivities and specificities. Direct comparison of these tests is not possible because no identified studies compared both genotyping and HBT/LTT with the criterion standard of duodenal mucosal biopsy. Indirect comparison is not possible because of the small number of studies comparing genotyping, HBT or LTT with biopsy. 

Incomplete agreement between genotyping for lactase insufficiency and indirect tests of lactose malabsorption is expected because these tests do not measure the same parameters. LTT and HBT are intended to diagnosis lactose malabsorption, which can be caused by factors other than lactase insufficiency. Additionally, because lactase activity persists for years after weaning, the inclusion of children can affect the concordance between HBT/LTT and genotyping. Di Stefano et al. (2009) found that the overall κ value for agreement of HBT and genotyping was 0.74, but for those younger than and older than 30 years of age, κ values were 0.56 and 1.0, respectively (p<0.005 for both comparisons).14 

In addition, the SNP -13910 C>T is not the only MCM6 polymorphism implicated in regulating transcription of the LCT gene. A study by Eadala et al. (2011) recruited patients with inflammatory bowel disease along with healthy control patients and found that although the C/C genotype was strongly associated with experiencing symptoms of lactose intolerance after HBT, there was a high proportion of lactose sensitivity in C/T and T/T genotype patients, as well.15 A 2012 Colombian study by Mendoza-Torres et al. found low specificity (46 percent) when comparing HBT with genotyping.16 The authors attributed this to the genetic heterogeneity of the Colombian and Caribbean population studied and recommended against using genotyping to assess lactase insufficiency in this population. Similarly, Santonocito et al. (2015) found a similar proportion (≈80 percent) of homozygous genotypes for lactase nonpersistence among 1,426 patients with gastrointestinal symptoms and 1,000 healthy volunteers in south central Italy.17 These results suggest that unmeasured genetic variation may more fully explain lactase insufficiency. 

Table 3. Sensitivity and Specificity of Analysis of the Genotyping Compared with HBT, LTT and Intestinal Biopsyª

Author (Year), Country

N

Sensitivity (95% CI)

Specificity (95% CI) 

Targeted mutation analysis of SNP -13910 C>T compared with HBT 

Gugatschka, 2005, Austria18 51   90 (73-98)   95 (76-100)  
Buning, 2005, Germany19   166   98 (93-100)   83 (71-91)  
Hogenauer, 2005, Austria9   123   97 (86-100)   86 (77-93)  
Bulhoes, 2007, Brazil20  20   90 (55-100)   100 (69-100)  
Schirru, 2007, Italy21 84   84 (72-93)   96 (81-100)  
Bernardes, 2007, Brazil22   147   76 (59-89)   100 (40-100)  
Szilagyi, 2007, Canada23   30   93 (68-100)   80 (52-96)  
Kerber, 2007, Austria24  120   97 (86-100)   72 (61-95)  
Mattar, 2008, Brazil25  50   96 (82-100)   100 (85-100)  
Krawcyk, 2008, Germany26  58   100 (78-100)   95 (84-99)  
Mottes, 2008, Italy27    112   71 (60-80)   83 (61-95)  
Waud, 2008, Wales28   200   100 (88-100)   64 (57-71)  
DiStefano, 2008, Italy14   32   88 (70-98)   100 (54-100)  
Nagy, 2009, Hungary29   186   77 (68-85)   94 (87-98)  
Szilagyi, 2009, Canada30 57   97 (83-100)   93 (76-99)  
Babu, 2010, India31  153   87 (80-93)   97 (85-100)  
Pohl, 2010, Germany32   194   90 (80-96)   98 (94-100)  
Mendoza-Torres, 2011, Colombia16  126   97   46  
Morales, 2011, Chile33 51   96.3   87.5  

Targeted mutation analysis of SNP -13910 C>T compared with H/MBT

Enko (2015), Austria13   263 79  87

Targeted mutation analysis of SNP -13910 C>T compared with LTT 

Nilsson, 2004, Sweden34   35   100   88  
Gugatschka, 2005, Austria18  46   85   90  
Ridefelt, 2005, Canada35  51   90   95  
Szilagyi, 2007, Canada23   30   93   87  
Babu, 2010, India31 153   97   87  

Targeted mutation analysis of -13910 C>T compared with biopsy-determined lactase activity

Rasinpera, 2004, Finland36   329
 
<5 Y: 109
 
6-11 Y: 142
 
>12 Y: 78  
--
 
80
 
94.6
 
93.3  
--
 
65.4
 
81.9
 
100  
Nilsson, 2004, Sweden34   35   100   88  
Kuchay, 2011, India37   176
 
Children >5: 108
 
Children >8:  NR
--
 
96
 
97.2  
--
 
78.9
 
100  
Targeted mutation analysis of -22018 G>A compared with HBT    

Bernardes (2007), Brazil22 

147  73  82 

Kerber (2007), Austria24 

166 100  71 

DiStefano (2009), Italy14 

123 89  100 

CI: confidence interval; HBT: hydrogen breath test; H/MBT: hydrogen methane breath test; LTT: lactose tolerance blood test; NR: not reported; SNP: single nucleotide polymorphism.
a There was heterogeneity in how HBT/LTT tests were conducted (e.g., using 25 g or 50 g of lactose) and in populations tested (e.g., inclusion of children or racial/ethnic composition of study populations). 

A 2012 meta-analysis by Marton et al. compared the diagnostic accuracy of HBT/LTT testing and -13910 C>T genotyping for prediction of lactase insufficiency phenotype.39 Seventeen studies evaluated HBT, and five evaluated LTT. Overall sensitivity and specificity of HBT was 88 percent (95 percent confidence interval [CI], 85 to 90) and 85 percent (95 percent CI, 82 to 87), respectively. Both sensitivity and specificity showed substantial heterogeneity (I2=78 percent and 87 percent, respectively), and the authors detected potential publication bias. For LTT, overall sensitivity was 94 percent (95 percent CI, 90 to 97) and specificity was 90 percent (95 percent CI, 84 to 95). No significant statistical heterogeneity was observed. Three studies also assessed the -22018 G>A genotype, which has been described in European populations, and found less accurate overall sensitivity and specificity (87 percent [95 percent CI, 79 to 93] and 76 percent [95 percent CI, 67 to 83], respectively) compared with the - 13910 C>T polymorphism.  

Clinical Utility
Clinical utility is how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes. No studies were identified that attempted to demonstrate improved patient outcomes or changes to patient management because of genetic testing for lactase insufficiency.

Lactase insufficiency is the normal phenotype for most adults, and a confirmatory diagnosis with HBT, LTT or genotyping is generally unnecessary. Empiric diagnosis by dietary restriction is adequate in most circumstances because this is the primary treatment for lactase insufficient patients. Patients who achieve satisfactory symptom control after dietary modification require no further diagnostic testing. For most patients who do not achieve symptom control after dietary modification, testing is indicated for the presence of other conditions that can cause similar symptoms.

The proposed clinical utility of genotyping for lactase insufficiency is that the test offers a more comfortable assessment for patients when compared with HBT, LTT or biopsy. Traditional testing methods may be associated with discomfort caused by the ingestion of a large volume of lactose, and there is dietary preparation and fasting before testing. Additionally, factors that may cause false-positive HBT and LTT results will not cause false-positive genotype results. Arroyo et al. (2010) suggested that genetic testing, when used with HBT, can help in the diagnosis of secondary hypolactasia when there is a positive HBT and the patient is not -13910 C/C genotype.40 

Summary of Evidence
Studies have demonstrated a high correlation between a single nucleotide polymorphism, -13910 C>T upstream of the gene encoding the enzyme lactase, and lactase insufficiency in persons of European ancestry. Studies in white populations report a high degree of agreement for the diagnosis of lactase insufficiency between genotyping and both hydrogen breath test (HBT) and lactose tolerance blood test (LTT).

Genetic testing has the potential advantage of sparing patients the discomfort of fasting and experiencing symptoms of lactose intolerance during the administration of HBT or LTT. Genotyping also may have additional utility in the diagnosis of secondary hypolactasia.

However, there is no current treatment for lactase insufficiency, and management involves dietary restriction and palliation of lactose intolerance symptoms. Therefore, an empiric diagnosis of lactose intolerance in the absence of confirmation by HBT, LTT or genotyping, followed by treatment with dietary restriction of lactose, is suitable. Currently there is insufficient evidence that the assessment of the genetic etiology of lactose intolerance would affect patient management or improve clinical outcomes. The use of targeted mutation analysis of -13910 C>T for the prediction of lactase insufficiency is, therefore, considered investigational.

Practice Guidelines and Position Statements
No guidelines or statements were identified.

U.S. Preventive Services Task force
Not applicable.

References

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  37. Kuchay RA, Thapa BR, Mahmood A, Mahmood S. Effect of C/T -13910 cis-acting regulatory variant on expression and activity of lactase in Indian children and its implication for early genetic screening of adult-type hypolactasia. Clin Chim Acta. Oct 9 2011;412(21-22):1924-1930. PMID 21763294
  38. Mattar R, Basile-Filho A, Kemp R, Santos JS. Comparison of Quick Lactose Intolerance Test in duodenal biopsies of dyspeptic patients with single nucleotide polymorphism LCT-13910C>T associated with primary hypolactasia/lactase-persistence. Acta Cir Bras. 2013;28 Suppl 1:77-82. PMID 23381829
  39. Marton A, Xue X, Szilagyi A. Meta-analysis: the diagnostic accuracy of lactose breath hydrogen or lactose tolerance tests for predicting the North European lactase polymorphism C/T-13910. Aliment Pharmacol Ther. Feb 2012;35(4):429-440. PMID 22211845
  40. Arroyo MA, Lopes A, Piatto V, Maniglia J. Perspectives for Early Genetic Screening of Lactose Intolerance: -13910C/T Polymorphism Tracking in the MCM6 Gene. The Open Biology Journal. 2010;3:66-71

Coding Section

Codes Number Description
CPT 81400

Molecular pathology procedure, level 1 (e.g., identification of single germline variant [e.g., SNP] by techniques such as restriction enzyme digestion or melt curve analysis) includes the following test effective 07/01/13:

LCT (lactase-phlorizin hydrolase) (e.g., lactose intolerance), 13910 C>T variant

ICD-9-CM Diagnosis 

 

Investigational for all relevant diagnoses 

ICD-10-CM (effective 10/01/15)   

Investigational for all relevant diagnoses 

ICD-10-PCS (effective 10/01/15)   

Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests. 

Type of Service     
 Place of Service    

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

Appendix

Appendix Table 1. Categories of Genetic Testing Addressed in Policy No. 20494

Category Addressed
  Yes   No

1. Testing of an affected individual’s germline to benefit the individual

     
     1a. Diagnostic X    
     1b. Prognostic     X
     1c. Therapeutic     X

2. Testing cancer cells from an affected individual to benefit the individual

     
     2a. Diagnostic     X
     2b. Prognostic     X
     2c. Therapeutic     X

3. Testing an asymptomatic individual to determine future risk of disease

    X

4. Testing of an affected individual’s germline to benefit family members

    X

5. Reproductive testing

     
    5a. Carrier testing: preconception     X
    5b. Carrier testing: prenatal     X
    5c. In utero testing: aneuploidy     X
    5d. In utero testing: mutations     X
    5e. In utero testing: other     X
    5f. Preimplantation testing with in vitro fertilization     X

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2014 Forward     

07/18/2018 

Annual review, no change to policy intent. 

07/12/2017 

Annual review, no change to policy intent. 

04/25/2017 

Updated category to Laboratory. No other changes 

06/01/2016 

Annual review, no change to policy intent. 

06/22/2015 

Annual review, no change to policy intent. Updated background, description, rationale and references. Added coding, guidelines and appendix 1. 

06/12/2014

Annual review, no changes made.


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