Lactose Intolerance and Health

Full Title: Consensus Development Conference: Lactose Intolerance and Health

Evidence-based Practice Center (EPC) Systematic Review Protocol

Report Expected Release Date: late 2009

Contents

Background
Key Questions
Analytic Framework
Methods
References
Definition of Terms
Explanation of Protocol Amendments
Review of Key Questions
Technical Expert Panel (TEP)
Peer Review (Standard Language)

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I. Background

Milk, and some dairy products, contains high concentrations of the disaccharide lactose (galactose and glucose linked by a ß-galactoside bond). Lactose ingestion in certain susceptible individuals can cause abdominal symptoms. Such symptoms include abdominal pain, bloating, excess flatulence, and diarrhea. The condition is believed to be due to a deficiency in the small intestinal enzyme lactase required for lactose absorption or to the amount or form of lactose consumed. This clinical scenario is described as lactose intolerance (LI). Symptoms believed due to LI are common, manifest in children or adolescence and appear to vary by race/ethnicity. Additionally, the amount of lactose ingestion that results in patient reported symptoms is quite variable. LI is typically treated with either a diet restricting lactose intake or providing enzymatic replacement.

The physiologic rationale behind lactose malabsorption and lactose intolerance is as follows: In the disaccharide form, lactose cannot be absorbed by the small bowel and passes into the colon where it may cause symptoms of lactose intolerance. Absorption requires hydrolysis of lactose to its constituent monosaccharides via the action of a ß-galactosidase (lactase-phlorizin hydrolase), an enzyme located in the brush border of the small intestinal mucosa. Roughly 70 percent of the world's adult population has insufficient brush border lactase to completely digest even small doses of lactose, thus the majority of the adult population malabsorbs lactose.

However, not all individuals who malabsorb lactose have symptoms. Additionally, symptoms of LI are similar to those caused by irritable bowel syndrome (IBS). A public health problem arises when large numbers of individuals, especially within minority groups, diagnose themselves as being LI. The problem becomes intergenerational when self-diagnosed lactose intolerant parents place their children on lactose restricted diets (even in the absence of symptoms) or use enzymatic replacement in the belief that the condition is hereditary. Since lactose-restricted diets are deficient in calcium, they may have significant effects on bone health in childhood and later on in adulthood, especially in postmenopausal women. Studies have shown that about one-third of self-identified lactose intolerant individuals are actually lactase persisters. Some of these lactase persisters (and even lactase nonpersisters) may mistakenly ascribe the symptoms of undiagnosed IBS or other intestinal disorders to LI.

Thus, differentiating lactose-induced symptoms from those of IBS requires demonstration that a physiological dose of lactose causes symptoms or removal of lactose from the diet reduces symptoms. Given that the relatively non-specific abdominal symptoms caused by IBS and lactose malabsorption are extremely susceptible to the placebo effect, reliable demonstration of lactose intolerance requires double-blind methodology. In contrast to the relatively enormous quantity of information available concerning lactose malabsorption, only a limited number of blinded studies of lactose intolerance have been performed. 

Understanding the terminology of lactose-related "problems" is important and outlined as follows:

1. Lactase deficiency—low concentrations of lactase in the small intestinal brush border relative to the concentrations observed in infants.
2. Lactose malabsorption—failure of the small bowel to absorb the bulk of an ingested load of lactose.
3. Lactose intolerance—a symptomatic response to malabsorption of lactose.

Lactase deficiency—There are multiple causes of lactase deficiency. Congenital lactase deficiency, a very rare condition in which lactase synthesis is negligible at birth, results from the inheritance of two defective alleles of the lactase transcribing gene located on chromosome 2. Secondary lactase deficiency occurs in diseases that damage the brush border, such as celiac disease or intestinal infections. This deficiency usually is reversible with recovery from the disease. Lactase non-persistence is a condition in which lactase synthesis is normal at birth and throughout infancy. However, after weaning lactase synthesis declines and by adulthood brush border lactase concentrations are only about 10 percent of the infantile level. This non-persistence of lactase synthesis, which occurs despite continued exposure to milk or lactose, is present in about 70 percent of the world's adult population. This review will focus solely on the problems associated with lactase non-persistence.

Lactase non-persistence versus persistence has been shown to be a function of a lactose promoter region located upstream from the lactase gene. In lactose non-persistent subjects, the activity of this promoter is programmed to decline markedly after weaning, with a resultant decline in lactase synthesis. Several population groups, most prominently individuals of northern European extraction, have mutations of this promoter which permits it to remain active throughout life. In northern Europeans, a single nucleotide thymine for cytosine substitution in the promoter region allows this gene to retain activity throughout adulthood with resultant lactase persistence. Lactose non-persisters have a C/C genotype whereas persisters have a C/T or T/T genotype (the CZ→T mutation is a dominant trait). 

Direct assessment of brush border lactase levels requires analysis of biopsies of small bowel mucosa via either measurement of enzymatic activity or histochemical staining for lactase. Genetic assessment of the C/T promoter area recently has become available. The complexity and expense of these techniques has limited their application, and information concerning the lactase non-persistence/persistence state of individuals largely has been inferred from measurements of lactose absorption. The Digestive Diseases Clearinghouse of the National Institute of Diabetes, Digestive and Kidney Diseases states that 30 million to 50 million individuals in this country and about 4 billion people worldwide are lactase non-persisters. Many of these individuals belong to minority groups such as Asians, African Americans, Hispanics, Native Americans, Alaskan Natives, and Pacific Islanders. However, lactase non-persistence is also observed in a sizable fraction of Caucasians of southern European and Mediterranean origin.

Lactose malabsorption—Multiple tests have been employed to assess the ability of a subject to absorb lactose. Such testing initially employed measurements of the rise in blood glucose observed after ingestion of a large (50 g) dose of lactose, the lactose content of one quart of cow's milk. A rise of blood glucose of <20 mg percent was used as evidence of lactose malabsorption. This test largely has been supplanted by the breath hydrogen (H₂) test, which assesses breath H₂ concentration following lactose ingestion. A rise in breath H₂ signifies that lactose has reached the colonic bacteria and hence was malabsorbed. Various lactose dosages, times of breath collection, and breath H₂ increases have been employed in this test, and the accuracy of breath H₂ testing for lactose malabsorption has never been precisely determined. Nevertheless, this simple noninvasive test has been widely employed and much of our knowledge concerning the prevalence of lactose malabsorption in various population groups as well as the ability of individual patients to absorb lactose has been obtained via breath H₂ testing.

Lactose intolerance—Lactose intolerance indicates that malabsorption of lactose results in symptoms of diarrhea, flatulence, bloating or abdominal discomfort. While lactose malabsorption and lactose intolerance frequently are used interchangeably, the demonstration that an individual malabsorbs lactose does not necessarily indicate that the subject will be symptomatic. The likelihood that a lactose malabsorber will perceive symptoms after ingestion of lactose is a function of many variables including the dosage of lactose, lactase activity of the mucosa, foods co-ingested with the lactose, the lactose fermentation pathways of the colonic flora, and the sensitivity of an individual's colon to lactose malabsorption. Of particular importance is the dosage of lactose. Intolerance to supra-physiological loads of lactose (such as were employed in the lactose tolerance test) does not necessarily indicate that subject will be symptomatic with a smaller, more physiological dosage. Thus, the dosage of lactose that causes symptoms is a major consideration in the determination of the importance of lactose as a clinical problem.  Another important question is the extent to which the colon of select individuals might be particularly sensitive to lactose and/or its bacterial metabolites, e.g., are patients with irritable bowel syndrome (IBS) unusually susceptible to lactose-induced symptoms.

Treatment of lactose intolerance—Lactose intolerance may be self-diagnosed or diagnosed by a clinician based on historical information and/or the demonstration of lactose malabsorption. Blinded evaluation to document the role of lactose in a patient's symptomatology is not employed. As a result, the subject's unblinded response to a reduction in lactose intake is the standard means of establishing the diagnosis of lactose intolerance in clinical practice. Treatment to reduce lactose exposure consists of a lactose restricted diet or the use of lactase supplements. The former may involve the avoidance of milk and milk-containing foods or the use of milk in which the lactose has been pre-hydrolyzed via treatment with lactase. Lactase supplements taken at the time of milk ingestion also are commercially available. Osteoporosis and associated fractures secondary to inadequate dietary calcium is the major potential health problem associated with real or assumed lactose intolerance, since the avoidance of milk and milk containing products usually results in a dietary calcium intake that is well below recommended levels of 1,000 mg per day for men and women and 1,300 mg for adolescents. Because dairy foods are the major source of dietary calcium intake (in the absence of supplementation) dietary recommendations suggests consuming 3 cups/day of fat free or low-fat milk or equivalent milk products. This amount could be ingested over the course of the day (e.g., 1 cup three times per day with each meal) to minimize potential problems with larger acute lactose loads.

Topic Nominator/Partner: The Agency for Healthcare Research and Quality (AHRQ) has requested an evidence report on the above topic as background material for and NIH Consensus Development Conference.

Food and Drug Administration (FDA) status: No drugs have been approved for LI.

Indications for LI: RIFAXIMIN, loperamide

Over-counter lactase preparations include (beta-D-galactosidase, Lactaid, Lactase N, Dairy Ease, Lactrase, Lactogest) and probiotics including Lactobacillus acidophilus BG2FO4; Bifidobacterium longum.

No warnings have been identified at present for use of any drugs or dietary supplements covered in the systematic review.

Project Time Line

Project Start Date: December 22, 2008
Anticipated Draft Report Due Date:  September 1, 2009
Anticipated Report Publication Date:  December 1, 2009

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II. Key Questions

1. What is the prevalence of lactose intolerance? How does this differ by race, ethnicity and age?
2.   What are the health outcomes of dairy exclusion diets?
   • In true lactase non-persisters?
   • In undiagnosed or self-identified lactose-intolerant individuals?
   • How does this differ by age and ethnicity?
   • Health outcomes to include: Bone health—osteoporosis, fracture, bone density, bone mass; and gastrointestinal symptoms— abdominal pain, diarrhea, nausea, flatulence, bloating.
3.   What amount of daily lactose intake is tolerable in subjects with diagnosed lactose intolerance?
   • How does this differ by age and ethnicity?
   • What are the diagnostic standards used?
4.   What strategies are effective in managing individuals with diagnosed lactose intolerance?
   • Commercially-available lactase.
   • Prebiotics and probiotics.
   • Incremental lactose loads for colonic adaptation.
   • Other dietary strategies.
5. What are the future research needs for understanding and managing lactose intolerance?

Question 1

Population(s): Persons older than 4 years of age.

Condition(s): We propose to define LI as a clinical syndrome of one or more of the following: abdominal pain, diarrhea, nausea, flatulence and/or bloating limited to ingestion of lactose or lactose-containing food substances of a quantity that is either desired by the individual or is necessary to meet Institute of Medicine daily dietary standards for calcium intake (for example, if reduced fat milk is used to meet the ~1200 mg recommendation of calcium, then approximately 45 g per day of lactose would need to be consumed (http://digestive.niddk.nih.gov/ddiseases/pubs/lactoseintolerance/).

We propose to exclude congenital lactase deficiency, developmental lactase deficiency among pre-term infants, milk allergies commonly seen in infants, acute lactose intolerance (<30-60 days duration) due to e.g., antibiotic use or illness (though would provide a discussion regarding the issues related to these).

Disease severity: We propose to define severity of lactose malabsorption according to the amount of consumed lactose (desired or required to meet established dietary needs) before experiencing clinical symptoms of lactose intolerance.

We also plan to analyze severity of lactose intolerance according to criteria from diagnostic tests:

Lactose intolerance breath test: increase from baseline in Hydrogen + Methane (in ppm) by 20-38 ppm as mild and >39 as severe lactose intolerance

We plan to define primary LI with genetic testing using restriction fragment length polymorphism or by DNA Sequencing to detect single-nucleotide polymorphisms (C-13910T, G-22018A) located upstream of the lactase gene within the gene MCM6.

We plan to review differences in prevalence estimates based on different definitions of LI:

• Primary lactase deficiency, a genetically determined decrease or absence of lactase is noted, while all other aspects of both intestinal absorption and brush border enzymes are normal. Primary lactase deficiency is attributable to relative or absolute absence of lactase that develops in childhood at various ages in different racial groups and is the most common cause of lactose malabsorption and lactose intolerance. Primary lactase deficiency is also referred to as adult-type hypolactasia, lactase nonpersistence, or hereditary lactase deficiency.
• We exclude the patient with secondary lactase deficiency occurs in association with small-intestinal mucosal disease with abnormalities in both structure and function of other brush border enzymes and transport processes. Secondary lactase deficiency is often seen in celiac sprue.

Lactose malabsorption is the physiologic problem that manifests as LI and is attributable to an imbalance between the amount of ingested lactose and the capacity for lactase to hydrolyze the disaccharide.¹

Comorbidities, patient demographics. We will review difference in prevalence of LI in patients of different age groups defined as:

Infants: 1-23 months, Preschool Children: 2-5 years, Children: 6-12 years, Adolescents: 13-18 years; Adults: 19-44 years, Middle Aged: 45-64 years, Aged: 65+ years, Elderly adults: 80 and over: 80+ years.

We will review differences in prevalence of lactose intolerance in patients of difference race and ethnic groups defined as:

Variable	Definition
Race
African Continental Ancestry Group	Individuals whose ancestral origins are in the continent of Africa.
Asian Continental Ancestry Group	Individuals whose ancestral origins are in the continent of Asia.
European Continental Ancestry Group	Individuals whose ancestral origins are in the continent of Europe.
Ethnic groups
African Americans	Persons living in the United States having origins in any of the black groups of Africa.
Arabs	Members of a Semitic people inhabiting the Arabian peninsula or other countries of the Middle East and North Africa. The term may be used with reference to ancient, medieval, or modern ethnic or cultural groups.
Asian Americans	Persons living in the United States having origins in any of the original peoples of the Far East, Southeast Asia, or the Indian subcontinent.
Hispanic Americans	Persons living in the United States of Mexican (Mexican Americans), Puerto Rican, Cuban, Central or South American, or other Spanish culture or origin. The concept does not include Brazilian Americans or Portuguese Americans.

We will include studies of patients with lactose intolerance and all comorbidities but acute diseases, treatment of which could cause secondary lactose intolerance.

Outcomes: Prevalence of LI.

We will report prevalence according to:

1. Patient reported diagnosis of LI.
2. Clinician diagnosis of LI.
3. Absolute difference in prevalence of individuals with symptoms as derived from randomized controlled blinded trials conducted in subjects diagnosed with LI.

We will compare outcomes between individuals with a diagnosis of LI receiving blinded lactose (at varying doses) and control interventions as well as the outcome from blinded randomized controlled trials comparing outcomes in subjects with diagnosed LI versus control subjects. We will assess the prevalence of lactose malabsorption by evaluating studies using breath hydrogen measures.

Glucose tolerance testing is rarely use clinically today and studies assessing this method for evaluating lactose malabsorption will be excluded. Studies assessing only intestinal biopsies will be reviewed for quality and applicability are unlikely to be relevant to the current clinical diagnosis and management of patients suspected of having LI though will be used to provide contextual information regarding the prevalence of lactase deficiency.

A critical aspect of this question will be to clearly define and differentiate between:

1. Lactase nonpersisters.
2. Lactose malabsorbers.
3. Lactose intolerance.

LI is the key component of this question and conference. Identifying a gold-standard definition of LI is critical and difficult. There is no objective laboratory test (intestinal biopsies are rarely done and only assess lactase enzyme levels; physiologic tests: e.g., hydrogen breath tests measure lactose malabsorption to a laboratory challenge and need to be evaluated to determine whether they accurately identify clinically relevant LI.

We are defining as a gold-standard definition of lactose intolerance: patient reported symptoms that occur when patients consume an amount of lactose less than or equal to a minimal daily requirement and at a greater frequency than placebo (or among nonLI controls) in randomized blinded controlled trials, resolve when lactose is removed and recur when lactose at a level meeting daily requirement levels is "blindly" reintroduced. 

We will evaluate prevalence according to different populations and methods of assessment with a particular focus on presence or absence of specific symptoms among individuals participating in blinded randomized controlled trials evaluating lactose intolerance. While assessing prevalence in randomized controlled trials typically is not done to assess prevalence we believe that patient reported symptoms and resolution of symptoms in the absence of placebo controlled trials are not reliable.

Question 2

Target population is defined as for question 1. We will distinguish the outcomes among patients with a medical or self-reported diagnosis of LI (even in the absence of confirmatory lactose challenges as noted above) from those not diagnosed with LI but who consume dairy exclusion diets. We will review both short and long-term health outcomes and the "natural history" of symptoms.

Interventions: We will define dairy exclusion diets as low-lactose diet that generally eliminates only milk and milk products or lactose-free diet that eliminates all lactose products, including foods that are prepared with milk, both at home and in commercially packaged foods. We will include studies with the following comparators: placebo or regular diet. We define interventions when the patients followed lactose free diets prescribed by the health care professionals. We define exposure when the subjects followed low lactose or lactose free diets without recommendations from health care professionals.

Outcomes:

• Primary outcomes: Fracture.
• Secondary outcomes: Osteoporosis, bone density, bone mass.
• Symptoms of lactose intolerance: Abdominal pain, diarrhea, nausea, flatulence and/or bloating.
• Morbidity:
  • Adverse events: All published adverse events.
• Timing: Duration of followup. We will include prospective and retrospective studies with duration of followup long enough to detect differences in outcomes (1-2 years for secondary outcomes (bone density) and 5 years for fracture. We will evaluate the impact of lactose exclusion diets on shorter-term (<6 months) patient reported symptoms from observational and interventional studies among individuals with both LI and nonLI controls.
• Settings: Primary and specialty outpatient settings, population based settings.
• Co-interventions: All co-interventions in studies that reported patient outcomes after low-lactose and lactose free diets will be reviewed.

We have conducted a literature search to identify three types of the studies:

1. Studies in patients with LI who followed lactose free diets.
2. Studies that examined patient outcomes among healthy populations consuming dairy exclusion (or very low dairy) diets (e.g., lacto-ova vegetarians).
3. Meta-analyses  and systematic reviews that synthesized the association between  dairy (dietary Ca++) intake and patient outcomes.

 With regard to outcomes beyond symptoms the TEP noted that the main health concerns related to lactose exclusion diets was predominately due to low Calcium and Vitamin D intake typically believed associated with these diets. Additionally they raised an issue related to impact of dietary or supplemental calcium and/or Vitamin D. The KQ addresses the role of dairy exclusion diets. We will review whether  the studies that examined patient outcomes in association with low dietary milk intake addressed Calcium intake from other sources and supplementation with  Ca++  or Vitamin D This will provide us with contextual information regarding the potential role of low lactose or lactose free diet on bone health independent of other sources of Ca++ or Vitamin D.

Question 3

Population(s): Target population is defined as for question 1 but limited to subjects with self or clinically diagnosed LI. We will focus on populations with clinically diagnosed LI.

We define genetic testing as reference methods to diagnose primary LI. We define LI breath test as methods for assessing lactose malabsorption. We define self-reported LI as the presence of self-described clinical symptoms occurring only when they ingest lactose and relieved when eliminating/reducing lactose or using products to hydrolyze lactose prior to ingestion. We will quantify the type and severity of symptoms and the amount and type of lactose causing patient reported symptoms. A presumptive working diagnosis of LI will be gastrointestinal symptoms associated with the ingestion of foods containing lactose that is either desired by the individual or considered necessary to meet national minimal daily dietary standards (see above), that resolve upon elimination or marked reduction of these lactose containing foods or using products to hydrolyze lactose prior to ingestion and, if data are available, return upon lactose rechallenge. We defined self reporting as index methods to diagnose LI.

Interventions: Individual daily or weekly intake of lactose that result in symptoms of LI stratified by presence or absence of Index diagnostic tests for LI. These individuals will either serve as their own controls or individuals without a LI diagnosis will be controls.

Comparators: Placebo, inactive comparator, lactose dose response

Outcomes:

• Primary outcomes: Gastrointestinal symptoms: Abdominal pain, diarrhea, nausea, flatulence and/or bloating prevalence and severity.
• Secondary outcomes: Diagnostic values of index methods to detect primary and secondary LI.
• Timing: short term (≤6 months) long-term (>6 months).
• Settings: primary and specialty outpatient settings, population-based settings.

We will primarily rely on an evaluation of results from blinded randomized controlled trials including dosing studies to determine the threshold amounts that cause symptoms in subjects with self or clinician diagnosed LI ingesting different doses of lactose vs. controls and the outcomes among individuals ingesting lactose with a diagnosis of LI versus nonLI controls. We will categorize findings according to age, ethnicity, and patient reported baseline LI severity and assess whether symptoms differ between subjects diagnosed with LI (self versus clinician) and controls.

We will characterize the diagnostic standards used in these studies (e.g., patient reported symptoms and breath hydrogen (measure of lactose malabsorption not LI). If there are gaps in evidence related to amount and type of daily lactose intake we will look for lower quality studies (case series, pre-post design, nonblinded studies) that provide patient report symptoms yet still minimize the risk of bias. Symptoms will be defined as patient reported: gas/flatulence, abdominal pain, bloating, and diarrhea.

Question 4

Population(s): Target population is defined as for question 1 but limited to subjects with diagnosed LI.

Interventions:

• Commercially-available lactase.
• Prebiotics and probiotics.
• Incremental lactose loads for colonic adaptation.
• Other dietary strategies.

Comparators: Placebo, usual care, no active treatment, or active control.

Outcomes for each question:

• Primary outcomes: Quality of life.
• Secondary outcomes: Frequency and severity of abdominal pain, diarrhea, nausea, flatulence and/or bloating.
• Adverse events: All published adverse events.
• Timing: All eligible studies with different duration of followup will be analyzed.
• Settings: Primary and specialty outpatient settings, population based settings.

Question 5

What are the future research needs for understanding and managing lactose intolerance? The TEP agreed that key gaps were likely to include studies require to accurately diagnose the overlapping symptoms of LI from other gastrointestinal (GI) disorders (especially irritable bowel syndrome); determine the health consequences of low lactose diets and identify methods to improve patient and provider information about the diagnosis and management of lactose intolerance versus other gastrointestinal symptom based conditions (especially functional bowel or celiac disease) versus lactose malabsorption. 

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III. Analytic Framework

We plan to follow the analytic framework (modified from USPSTF)² to determine causality between treatments and patient outcomes and adverse events in patient subpopulations including age, race, and ethnic subgroups. Probabilities of diagnosis, treatment, and outcomes will be analyzed based on the published literature.

Note: The figure also gives information about research questions:

• KQ1: What the prevalence of lactose intolerance?
• KQ2: What the intermediate and clinical outcomes of lactose free or low lactose diets?
• KQ3: What amount of daily lactose intake is tolerable in subjects with diagnosed lactose intolerance?
• KQ4: What the intermediate, clinical, and adverse outcomes after treatments for lactose intolerance?

In the clinical situation, a graduated definition of potentially lactose intolerant subject might be as follows:

1. The quantity of lactose routinely ingested by the individual that causes symptoms.
2. The quantity of lactose ingested in some situations by the individual causes the above symptoms.
3. The quantity of lactose that the individual would like to ingest (but does not due to fear of symptoms) causes the above symptoms.
4. The quantity of lactose ingested in the course of obtaining 1500 mg/day of calcium entirely via lactose-containing dairy products causes above symptoms.

A confounding problem is that factors other than simply the quantity of lactose ingested might influence a subject's symptomatic response, i.e., the form in which lactose is ingested (ice cream versus milk, etc.), the coingestion of non-lactose containing foods, the nonspecificity of symptoms and the large placebo response potentially observed.

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IV. Methods

A. Criteria for Inclusion/Exclusion of Studies in the Review

We will conduct a literature review to find original epidemiologic studies of prevalence and management of lactose intolerance.

• Inclusion criteria: original observational studies that examined prevalence, symptoms, and outcomes of LI in different age, gender, racial, and ethnic groups; published in English language; randomized controlled clinical trials that examined different treatment options in patients with LI, published and presented in the national and international scientific meetings or in dissertations; large observational therapeutic studies in patients with LI that performed at least one strategy to reduce bias. We will limit our search to studies published after 1970. We will exclude studies that were published in non English languages and small case reports or descriptive case series with less than 100 subjects unless there are no reliable data from other higher quality studies. We will emphasize US based population studies.

We do not plan to review grey literature. We may contact the authors to clarify unreported quality components or ambiguous data.

For KQ1, large population based studies will be included. Smaller studies that meet quality criteria will be included if they are judged necessary to address gaps in evidence for the question. Criteria for populations will include primary lactose intolerance with an important distinction between lactose malabsorption from lactose intolerance. For KQ1, we will focus on populations most relevant to the U.S. though this may require including studies from other countries if needed to assess racial/ethnic findings. Individuals with secondary lactose intolerance will be excluded.

B. Searching for the Evidence: Literature Search Strategies for Identification of Relevant Studies to Answer the Key Questions

We will search several databases, such as MEDLINE®, Cochrane Database of Systematic Reviews and randomized controlled clinical trials and Scirus. We will review abstracts against pre-established inclusion/exclusion criteria to determine potential eligibility for inclusion in the evidence synthesis. We will retrieve and review full articles on eligible studies, extracting key data from each eligible study and entering the abstracted data into an electronic database.

An unknown number of these will not have a useable abstract available electronically. For these articles, we will retrieve abstracts from the original articles. The project manager, together with the expert clinical abstractors, will review all the abstracts to determine the eligibility of the articles for inclusion in the literature synthesis. To ensure consistency, all abstractors will attend a training session prior to beginning the abstract review step in which the inclusion/exclusion criteria will be presented and discussed. In addition, the project team, including the expert clinical abstractors, will meet after reviewing the first 25 abstracts, review their current status, discuss and minimize disagreements, and develop a standardized reviewing approach. Ensuring that all appropriate abstracts are included in our literature synthesis and that no significant ones are missed calls for other quality steps. To this end, the project director and project manager will re-review all abstracts that were determined to be ineligible after the initial review. In addition, we will randomly select a 10 percent sample of abstracts determined to be eligible for inclusion and subject them to rereview by the project director. Generally speaking, for all abstracts, we will err on the side of inclusion rather than exclusion. Once the abstracts have been reviewed for relevance, EPC staff will retrieve original articles for all studies that meet inclusion criteria. Each retrieved article will be read and abstracted onto evidence tables by an expert clinical abstractor. The project director will then reread the articles and check the abstracted information against the original article. We expect that, during the initial read of the full articles, many retrieved articles will not meet the inclusion/exclusion criteria. The project director will read and verify the exclusion of any such articles. We will develop a coding scheme to account for reasons for exclusion for later documentation. 

C. Assessment of Methodological Quality of Individual Studies

We will rate the quality of studies according to recommendations from the Methods Guide for Comparative Effectiveness Review

Stage 1. Classify the study design

1. Is the study comparative?
2. Did investigators assign the exposure?
   If so, was the intervention allocated randomly? Was randomization done at the individual level?
   If not, was more than one group of subjects studied? Were exposure and outcome assigned at the same time? Were groups assigned by exposure or by outcome?

Based on the answers to these questions, most studies can be classified as:

• Interventions: RCT (I) or non randomized controlled clinical trial (IA) or non randomized uncontrolled clinical trial.
• Observational:
  • Cohort (prospective) study with concurrent controls (II-2A). The study had defined populations which were prospectively followed in an attempt to determine distinguishing subgroup characteristics. The sufficient populations were observed over a sufficient number of years to generate incidence rates subsequent to the selection of the study group.
  • Cohort (retrospective) study with concurrent controls (IIC). The study had defined populations which were retrospectively followed in an attempt to determine distinguishing subgroup characteristics. The essential feature is that some of the persons under study have the disease or outcome of interest and their characteristics are compared with those of unaffected persons.
  • Case-controlled (retrospective) study. The study started with the identification of persons with a disease of interest and a control (comparison, referent) group without the disease. The relationship of an attribute to the disease was examined by comparing diseased and non-diseased persons with regard to the frequency or levels of the attribute in each group.
  • Cohort (prospective) study with historical controls (IIB). The study had defined populations which were prospectively followed in an attempt to determine distinguishing population characteristics with historical controls.
  • Nested case-control. The study started with the identification of persons with a disease of interest and a control (comparison, referent) group without the disease that were identified within the cohort of the subjects, participants in prospective cohort study. The relationship of an attribute to the disease was examined by comparing diseased and non-diseased persons with regard to the frequency or levels of the attribute in each group.
  • Cross-sectional study. The study determined the association with a disease at one particular time point before-after or interrupted time series; or non comparative study.

Stage 2. Abstract predefined criteria for quality for critical appraisal

We propose to evaluate quality of observational studies of prevalence of lactose intolerance using criteria of internal and external validity.

We propose to evaluate quality of interventional studies using criteria from the Methods Guide for Comparative Effectiveness Reviews, including randomization, adequacy of randomization and allocation concealment, masking of the treatment status, intention to treat principles, and justification of the sample size.

We will use the following ratings of Quality of Individual Studies:

• Well designed and conducted (good—low risk of bias). These studies have the least bias and results are considered valid. A study that adheres mostly to the commonly held concepts of high quality including the following: a formal randomized controlled study; clear description of the population, setting, interventions, and comparison groups; appropriate measurement of outcomes; appropriate statistical and analytic methods and reporting; no reporting errors; low dropout rate; and clear reporting of dropouts.
• Fair. These studies are susceptible to some bias, but it is not sufficient to invalidate the results. They do not meet all the criteria required for a rating of good quality because they have some deficiencies, but no flaw is likely to cause major bias. The study may be missing information, making it difficult to assess limitations and potential problems.
• Poor (high risk of bias). These studies have significant flaws that imply biases of various types that may invalidate the results. They have serious errors in design, analysis, or reporting; large amounts of missing information; or discrepancies in reporting.

We will also assess for external validity (applicability) according to the Methods Guide for Comparative Effectiveness Reviews.

D. Data Synthesis

We will summarize evidence into summary tables with qualitative analysis of the results for prevalence of LI by subgroups for question 1. We do not plan on pooling results for question 1. We may calculate odds ratio with 95 percent CI or absolute risk differences from the reported number of events in randomized controlled clinical trials as well as the number needed to treat to achieve one event of the outcome if the data are homogeneous enough to permit pooling. All additional calculations will be documented and performed at 95 percent confidence levels.

SEp=√  [p*(1-p)]/[n+4]; 95 percent level C confidence interval p±1.96*SEp

Where p = prevalence, n = sample size. Attributable risk will be calculated as the outcome events rate in patients exposed to different clinical interventions:^3-5 Attributable risk of the outcome = rate of events in patients in the control group x (relative risk -1). Number needed to treat to prevent one symptomatic event will be calculated as reciprocal to absolute risk differences in rates of outcomes events in the active and control groups:^4,6 1/(control group event rate - treatment group event rate).

The number of avoided or excess symptomatic events (respectively) per 1000 population is the difference between the two event rates multiplied by 1000: (control group event rate - treatment group event rate)*1000

We do not plan on pooling analysis for data related to Key question 1 or 2.

E. Grading the Evidence for Each Key Question

Assess Study Quality and Strength of Evidence. On the basis of the quality checklist(s) developed for articles relevant to the various key questions, the abstractor will assign a quality score to each article. We will use methods for assessing study quality and strength of evidence according to the Methods Guide for comparative Effectiveness Reviews which is conceptually similar to the GRADE system of evidence rating.^7,8 Specifically, we will assess four domains: risk of bias, consistency, directness, and precision. When appropriate we will also include dose-response association, presence of confounders that would diminish an observed effect, strength of association, and publication.

1. Quality of evidence across studies for each outcome.

   We will grade the quality of evidence for primary outcomes across studies according as illustrated in the table below:

Overall ranking of evidence

Grade	Definition
High	High confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect.
Moderate	Moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of effect and may change the estimate.
Low	Low confidence that the evidence reflects the true effect. Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate.
Insufficient	Evidence either is unavailable or does not permit a conclusion.

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V. References

1. Heyman MB. Lactose intolerance in infants, children, and adolescents. Pediatrics 2006 Sep; 118(3):1279-86.

2. Harris RP, Helfand M, Woolf SH, et al. Current methods of the U.S. Preventive Services Task Force: a review of the process. Am J Prev Med 2001 Apr; 20(3 Suppl):21-35.

3. Kahn HA, Sempos CT. Statistical Methods in Epidemiology (Monographs in Epidemiology and Biostatistics). U.S.A.: Oxford University Press; 1989.

4. Egger M, Smith GD, Altman DG. Systematic Reviews in Health Care. London: NetLibrary, Inc. BMJ Books; 2001.

5. Dawson B, Trapp RG. Basic & Clinical Biostatistics (LANGE Basic Science), 3rd ed. New York: Lange Medical Books-McGraw-Hill; 2004.

6. Ebrahim S. The use of numbers needed to treat derived from systematic reviews and meta-analysis. Caveats and pitfalls. Eval Health Prof Jun 2001;24(2):152-64.

7. Atkins D, Briss PA, Eccles M, et al. Systems for grading the quality of evidence and the strength of recommendations II: pilot study of a new system. BMC Health Serv Res 2005 Mar 23; 5(1):25.

8. Atkins D, Eccles M, Flottorp S, et al. Systems for grading the quality of evidence and the strength of recommendations I: critical appraisal of existing approaches The GRADE Working Group. BMC Health Serv Res 2004 Dec 22; 4(1):38.

9. Lactose Intolerance What You Need to Know. U.S.A. NIH Publication No. 06-2751. http://digestive.niddk.nih.gov/ddiseases/pubs/lactoseintolerance/. 2006.

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VI. Definition of Terms

Lactose malabsorption—Multiple tests have been employed to assess the ability of a subject to absorb lactose. Such testing initially employed measurements of the rise in blood glucose observed after ingestion of a large (50 g) dose of lactose, the lactose content of one quart of cow's milk. A rise of blood glucose of <20 mg percent was used as evidence of lactose malabsorption. This test largely has been supplanted by the breath hydrogen (H₂) test, which assesses breath H₂ concentration following lactose ingestion. A rise in breath H₂ signifies that lactose has reached the colonic bacteria and hence was malabsorbed. Various lactose dosages, times of breath collection, and breath H₂ increases have been employed in this test, and the accuracy of breath H₂ testing for lactose malabsorption has never been precisely determined. Nevertheless, this simple noninvasive test has been widely employed and much of our knowledge concerning the prevalence of lactose malabsorption in various population groups as well as the ability of individual patients to absorb lactose has been obtained via breath H₂ testing.

Lactose intolerance—Lactose intolerance indicates that malabsorption of lactose results in symptoms of diarrhea, flatulence, bloating or abdominal discomfort. While lactose malabsorption and lactose intolerance frequently are used interchangeably, the demonstration that an individual malabsorbs lactose does not necessarily indicate that the subject will be symptomatic. The likelihood that a lactose malabsorber will perceive symptoms after ingestion of lactose is a function of many variables including the dosage of lactose, lactase activity of the mucosa, foods co-ingested with the lactose, the lactose fermentation pathways of the colonic flora, and the sensitivity of an individual's colon to lactose malabsorption. Of particular importance is the dosage of lactose. Intolerance to supra-physiological loads of lactose (such as were employed in the lactose tolerance test) does not necessarily indicate that subject will be symptomatic with a smaller, more physiological dosage. Thus, the dosage of lactose that causes symptoms is a major consideration in the determination of the importance of lactose as a clinical problem. Another important question is the extent to which the colon of select individuals might be particularly sensitive to lactose and/or its bacterial metabolites, e.g., are patients with irritable bowel syndrome (IBS) unusually susceptible to lactose-induced symptoms.

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VII. Explanation of Protocol Amendments

The following protocol elements are standard procedures for all protocols.

VIII. Review of Key Questions

For Comparative Effectiveness reviews the key questions were posted for public comment and finalized after review of the comments. For other systematic reviews, key questions submitted by partners are reviewed and refined as needed by the EPC and the Technical Expert Panel (TEP) to assure that the questions are specific and explicit about what information is being reviewed.

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IX. Technical Expert Panel (TEP)

A TEP panel is selected to provide broad expertise and perspectives specific to the topic under development. Divergent and conflicted opinions are common and perceived as health scientific discourse that results in a thoughtful, relevant systematic review. Therefore study questions, design and/or methodological approaches do not necessarily represent the views of individual technical and content experts. The TEP provides information to the EPC to identify literature search strategies, review the draft report and recommend approaches to specific issues as requested by the EPC. The TEP does not do analysis of any kind nor contribute to the writing of the report.

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X. Peer Review (Standard Language)

Approximately five experts in the field will be asked to peer review the draft report and provide comments. The peer reviewer may represent stakeholder groups such as professional or advocacy organizations with knowledge of the topic. On some specific reports such as reports requested by the Office of Medical Applications of Research, National Institutes of Health there may be other rules that apply regarding participation in the peer review process. Peer review comments on the preliminary draft of the report are considered by the EPC in preparation of the final draft of the report. The synthesis of the scientific literature presented in the final report does not necessarily represent the views of individual reviewers. The dispositions of the peer review comments are documented and will, for Comparative Effectiveness Reviews (CERs) and Technical Briefs, be published three months after the publication of the Evidence Report.

It is our policy not to release the names of the peer reviewers or TEP panel members until the report is published so that they can maintain their objectivity during the review process. 

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Current as of June 2009

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Internet Citation:

Lactose Intolerance and Health, Systematic Review Protocol. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/tp/lacinttp.htm

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