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Nutrition and Diet in Surveillance and Registry Studies of Hemoglobinopathies

Executive Summary

August 23-24, 2010 Natcher Building, National Institutes of Health, Bethesda MD

Agenda

Introduction

The National Heart, Lung, and Blood Institute (NHLBI), the NIH Office of Dietary Supplements, and the NIH Office of Rare Diseases Research convened a Working Group entitled “Nutrition and Diet in Surveillance and Registry Studies of Hemoglobinopathies” on August 23-24, 2010, as part of the annual NHLBI Sickle Cell Disease Clinical Research Meeting in Bethesda, MD. The purpose of this Working Group was to:

  • Review the scientific evidence on macronutrients, micronutrients, nutritional status, and dietary adequacy in hemoglobinopathies patients;
  • Discuss consumers’ and clinicians’ concerns about nutritional status, dietary intake, and use of dietary supplements by hemoglobinopathy patients;
  • Review methods for the assessment of dietary intake, nutritional status, and use of nutritive and non-nutritive dietary supplements and discuss their application to sickle cell disease and the thalassemias; and
  • Identify research needs and opportunities in basic, translational, and clinical science.

Background

The hemoglobinopathies, sickle cell disease and thalassemias, are rare disorders caused by autosomal recessive mutations in one or more hemoglobin genes. Sickle cell disease (SCD) (http://www.nhlbi.nih.gov/health/health-topics/topics/sca/) is caused by mutations that induce hemoglobin to polymerize in the de-oxy state, which transforms normally flexible red cells into rigid, sickle-shaped cells. SCD is estimated to affect between 80,000-100,000 U.S. adults and children, who are primarily of African American descent although other racial and ethnic groups are also affected (Brousseau DC et al., 2010) (Hassell K, 2010). Patients with SCD often experience delayed growth and development, considerable physical disability, strokes, shortened lifespan, and cerebral infarcts that affect cognitive function thereby limiting education and employment opportunities. Sickled blood cells have a rapid turnover and a propensity to block small blood vessels, leading to an array of serious and sometimes life-threatening complications (e.g., skin ulcers, infections, stroke, and damage to the spleen, kidneys, eyes, lungs, bones, and other tissues and organs) that often are accompanied by severe pain. Treatments focus on controlling pain and lowering the risk and severity of complications. Therapeutic modalities for SCD include blood transfusions to treat anemia and to prevent stroke and its recurrence; hydroxyurea to reduce the frequency of painful crises and mortality; and in young children, penicillin prophylaxis to prevent severe infection.

Thalassemias are caused by mutations that lead to decreased production of globin chains that make up the hemoglobin molecule (http://www.nhlbi.nih.gov/health/health-topics/topics/thalassemia/). There are several hundred mutations that result in abnormal globin chain synthesis and the severity of disease depends on which mutation or combination of mutations is present. Alpha thalassemias are generally mild or asymptomatic and most often affect people of Southeast Asian, Indian, Chinese, or Filipino origin or ancestry. Four-gene deletion alpha thalassemia usually results in death in utero. The degree of anemia in the beta thalassemias syndromes ranges from mild (so-called “thalassemia intermedia”) to severe (major, also known as Cooley’s Anemia) and most often affect people of Mediterranean, Asian, or African origin or ancestry. Complications include musculoskeletal abnormalities, anemia, and shortened lifespan. Treatments are directed toward improving anemia (generally through transfusions), minimizing iron overload which can result from markedly increased iron absorption in non-transfused patients and from the blood transfusions, and monitoring for pulmonary hypertension. In North America, thalassemia major is a rare condition, affecting approximately 1100 individuals.

Sickle cell disease and thalassemia pose unusual nutritional challenges. For example, patients with sickle cell anemia are known to have increased dietary needs for multiple nutrients (e.g., zinc, folate, vitamin A energy, and protein) (Hyacinth et al., 2010) (Leonard et al.,1998) (Zemel et al. 2002) (Kennedy et al., 2001) (Barden et al., 2000) (Fung et al., 2001) (Schall et al., 2004) (Dougherty et al., 2012). Other inefficiencies of metabolism and low vitamin D status are frequently observed (Buison et al., 2004) (Buison et al., 2005) (Rovner et al., 2008). Growth and maturation often are delayed and do not mirror that of population age norms (Barden et al., 2002) (Zemel et al., 2007) (Dougherty et al., 2011). In addition, small studies suggest that these patients use complementary and alternative medicine, such as nutritional supplements to compensate for unmet nutritional needs but also herbal preparations for symptoms such as fatigue and pain (Post-White et al., 2009) (Tanabe et al., 2010). The potential for dietary imbalance is worsened by the demographics of the affected populations (primarily minorities and immigrants) that put the patients at economic risk of inadequate intake and may make it difficult to follow general guidance for healthy lifestyle (Laraia, 2013) (Holben and ADA, 2010) (Mitchell et al., 2004) (Kawchak et al., 2007).

Thalassemia patients who are inadequately transfused or have uncontrolled iron overload experience anemia, impaired skeletal growth, and delayed physical development. Inadequate intake of many nutrients exacerbates these complications. Dietary inadequacy for macro- and micronutrients tends to increase with increasing age. Fewer adults and children with thalassemia are overweight or obese compared to the U.S. population and children with thalassemia, particularly non-tranfused patients, tend to be underweight. Growth failure is multi-factorial due to chronic anemia, chelation toxicity, iron- and disease-associated endocrinopathies, and sub-optimal nutritional status and dietary intake. Thalassemia patients have bone problems (such as pain, fractures, osteopenia, and osteoporosis) as well as enlarged spleens and susceptibility to infection, reflecting the consequences of high red blood cell production rates and turnover (Fung et al., 2012) (Vogiatzi et al., 2009a) (Vogiatzi et al., 2009b).

In both conditions, treatment by blood transfusion leads to iron overload which can damage the liver, heart, and other organs (Gladwin and Sachdev, 2012). Iron overload potentially can be mitigated by chelation therapy, but these patients may require dietary adaptations to minimize iron absorption and foster red blood cell production (Claster et al., 2009).

There is a dearth of well-designed trials or pragmatic studies in nutritional interventions in the hemoglobinopathies. The need remains for adequately powered clinical studies to characterize children’s and adults’ nutritional status, as well as for basic, clinical, and translational research to provide a rational basis for potentially useful interventions.

II. Overview

Working Group participants reviewed key areas in nutrition and hemoglobinopathies and identified the most urgent knowledge gaps in light of current clinical and public health priorities.
Attendees had experience and content area expertise in nutrition and dietetics, epidemiology, behavioral sciences, patient advocacy, clinical hematology, pediatrics, cardiology, pathology, and molecular biology. A Consumer Workshop session held at the start of the meeting addressed patient and family concerns regarding nutrition and diet. Three Breakout Groups identified research priorities and resource needs in Basic Science and Pre-Clinical Research; Clinical Research; and Population Science and Implementation Research.
The agenda addressed five main areas:
1.) Nutritional physiology in hemoglobinopathies, including nutrient requirements, metabolism, and status assessment in sickle cell disease and thalassemias; exercise physiology and physical activity in hemoglobinopathy patients; one-carbon metabolism in hemoglobinopathies; metabolic assessment using metabolomics; endothelial dysfunction in sickle cell disease; and suitable animal models;
2.) Clinical nutrition in hemoglobinopathies, including nutrition counseling and dietetics practice in sickle cell disease and thalassemias, nutritional and non-nutritional dietary supplement usage patterns, and food insecurity and its relationship with chronic disease;
3.) Consumer and family priorities, including practical aspects of implementing guidance on nutrition and diet, dietary supplement use, and the role of diet and physical activity as components of self-care and disease management;
4.) Surveillance and registry studies, including principles and examples of surveillance and registry studies and resources for population science research; and
5.) Ancillary study designs and data collection models, including NHANES and other surveys, nested case-control designs, patient-reported outcomes in biomedical and behavioral research, and the connection between WIC enrollment and sickle cell disease experience.

III. Needs and Opportunities for Research and Resources

  • Basic and Pre-Clinical Science

Understanding the underlying mechanisms and etiology of the metabolic abnormalities, nutritional deficiencies, and response to interventions seen in hemoglobinopathies

  • There is a need to quantify intake, absorption, turnover rates, losses, excretion, and the metabolic pathways that affect nutritional status and requirements of hemoglobinopathies patients, for a better understanding of the pathogenesis of nutritional deficiencies (or excesses) in these patient populations. Problems with intake, absorption, and turnover rate are widespread and have major adverse effects on nutrient balance.
  • Supplementation for either individual nutrients or combinations (“cocktails”) should have a rational, science-based justification. The efficacy and safety of such interventions should be evaluated in conjunction with mechanistic animal and human studies. Safety should also be addressed for nutritional or botanical supplements taken with the aim of boosting energy, stamina, or physical performance.
  • Studies in humans and animals are needed of the biological impact of severe iron overload due to transfusions, including effects on absorption (or malabsorption) of other nutrients, especially minerals, and the nature of the relationship between generation of oxygen species and radicals, antioxidant status, free iron, and non-transferrin-bound iron. There is a need for improved methodologies to characterize the pathogenesis of iron overload (e.g., biomarkers) in order to develop and test intervention strategies to treat this condition.

Identifying suitable animal models for nutrition research

  • The potential utility of mouse and other animal models of hemoglobinopathies should be explored for addressing nutrition research questions. These models, which include knock-in and knock-out mouse models of SCD and humanized knock-in beta-thalassemia mice, consistently recapitulate the onset and progression of disease. A challenge in conducting research with these animal models is that it may be difficult to maintain a satisfactory breeding colony. Research topics could include characterization of the analogous metabolic changes and abnormalities, metabolic pathways, metabolite profiles, and nutritional issues (such as deficiencies) seen in humans. The animal models should provide an array of phenotypic and genetic variation that speaks to the heterogeneity of the human situation.

Taking advantage of available technologies and resources (metabolic methods, imaging technologies, and sample/data repositories)

  • Stable (non-radioactive) isotopes (such as deuterated compounds or C14 or stable isotopes of essential minerals Zn68) are potentially valuable for studying metabolic flux and other metabolic questions in hemoglobinopathies. Stable isotope protocols must allow sufficient resources and time for consent procedures and patient education.
  • Imaging studies (such as magnetic resonance imaging and magnetic resonance spectrometry) can be used to study effects of hypoxia or nutrient flux on brain and other tissues. Similarly, nitric oxide inhalation can be used to study vasodilation responses in patients.
  • Other potentially useful methods and measurements include backscatter ultrasonography, flow dynamics in vivo, red blood cell aggregation, and blood viscosity.
  • New metabolomics approaches now allow in-depth study of individual variability in the metabolic response to nutritional interventions and perturbations. Each person can have a unique average nutrient requirement and genetic variation, such as single nucleotide polymorphisms (SNP) that can alter nutrient requirements. Sickle cell disease and thalassemia have a complex nutritional picture, including altered requirements and turnover rates, which is difficult to study, in part due to the small number of patients and high variability in phenotypes. In this case, metabolomic profiling may be an avenue for developing a more comprehensive picture of individual differences in metabolism and their genetic basis. Targeted approaches to defining the metabolome include mass spectrometry, NMR, and informatics, along with cluster and principal component analysis. These approaches provide the tools necessary to delineate and describe observed differences.
  • Study designs need to plan for assay and data analysis of multiple analytes and biomarkers. This includes consideration of new genomics, metabolomics, or proteomics methodologies, as well as studies of the intestinal or lung microbiome. Array data need to be interpreted in light of functional outcomes. Better bioinformatics approaches are needed for data analysis and interpretation of research results, including understanding the relationship between array data and functional outcomes.
  • Ongoing human studies should bank DNA samples and possibly immortalize cells as well for future research endeavors, including new assays and data mining. This would be facilitated by centralized and consistent guidance (such as for informed consent procedures or certificates of confidentiality). Data and sample repositories, such as the NHLBI BioLINCC program (https://biolincc.nhlbi.nih.gov/home/), are potentially valuable resources for such research and can provide examples of protocols for consent and other issues.

Clinical and Translational Science

Clarifying the relationship between nutritional status and clinical outcomes, and identifying clinically helpful interventions

Practical concerns of patients and families often focus on how best to meet the basic elements of a nutritionally sound diet and ensure adequate food and fluid intake in the face of fluctuating appetite. Another concern is how best to identify oral nutritional and dietary supplements that would help the patient to meet specific nutrient needs.

Nutritional status assessment in hemoglobinopathies patients involves a clinical judgment integrating many streams of information: a) dietary intake(patterns of food consumption and supplement usage; usual appetite and any recent changes; whether the patient has missed meals or has a sense of food insecurity due to social and economic constraints); b) anthropometry (height, weight, and body mass index for age, assessed by comparison with standard growth curves; evidence of being underweight or overweight/obese for age or having growth retardation); c) sexual development by Tanner stage (if appropriate);and d) musculoskeletal health and physical functioning (bone density, lean body mass, grip strength, exercise capacity, and engagement in free-living physical activity). For any of these measurements, the time frame for assessment should be related to the research hypothesis or clinical question.

Laboratory assay for micronutrient status may also be needed as part of the assessment, although it is critical to ensure that the laboratory has suitable experience with these measurements as they may not be part of standard clinical panels, especially in critical care situations. Chronic or acute co-morbid conditions (such as malabsorption, diabetes, inflammatory disorders, and infections) also must be evaluated for their potential to impinge on nutritional status.

Dietary intake assessment for patients with hemoglobinopathies should collect information on both foods (i.e., description of items and quantities consumed) and also nutritional and non-nutritive supplements. Nutritional supplements include multivitamin-multimineral preparations, single nutrients, meal substitutes, protein powders, and amino acids. Non-nutritive supplements may include botanical or herbal preparations. Supplement intake should be assessed for a time frame of the past 30 days and should specifically request information on type, dose, frequency of use, and manufacturer; it often is helpful to have the patient or family member bring the bottle(s) to the interview. Numerous diet and supplement assessment methodologies are available for clinical and research use (Coulston et al., 2013). Some of these methods are suitable for clinic populations, although staff may need to set aside time to teach families how to use these tools.

Research and clinical practice needs include:

  • Interventional studies to enable the development of evidence-based best practices for nutrition-related management of hemoglobinopathies patients. It then would be possible to design surveys to determine adherence and outcomes.
  • Identifying and validating suitable biochemical and clinical biomarkers of nutritional status for patients with hemoglobinopathies and correlating these measures with clinical status. For many markers, it is not clear which data elements are the most informative, i.e., the best predictors of outcomes. To obtain adequate reference data, study designs should be longitudinal, have sufficient statistical power, and include a variety of age groups, as markers may vary with age. Measures might include:
  • anthropometric measurements (height, weight, head circumference) and body composition assessment (mass of adipose tissue, bone, lean muscle);
  • nutrient intake (calories, protein, fats, micronutrients);
  • micronutrient concentrations in blood and urine (spot, overnight, or 24-hour collections); nutrients such as folate, B12, B6, choline, and others involved in one-carbon metabolism; carotenoids and fat-soluble vitamins (A, D, E, K) and their isomers and metabolic intermediates; hematopoietic pathway minerals such as iron, zinc, and copper; bone minerals such as calcium, phosphate, and magnesium; and essential fatty acids.
  • stool samples (with attention to transit time and the potential need for 3-day collections) when evaluating nutrient absorption issues, particularly for energy and mineral status.
  • related measurements such as hormones involved with nutrient metabolism (e.g., parathyroid hormone for bone), inflammatory markers, and cardiovascular and thrombotic risk parameters (lipid profile, blood pressure, endothelial function, coagulation cascade).
  • Characterizing drug-nutrient interactions for commonly used medications. For example, hydroxyurea (used for sickle cell anemia) can adversely affect vitamin B12 status, and iron-chelating agents such as deferoxamine (used for thalassemia) can adversely affect trace mineral (zinc) status.
  • Understanding nutritional needs for pregnancy in hemoglobinopathies patients. There is little information on reproductive and pregnancy outcomes of hemoglobinopathy patient populations or on the relationship of nutritional status and diet (including drug-nutrient interactions) to these outcomes.
  • Clarifying the potential utility of nutrient supplementation for macronutrients and micronutrients. There has been little study of the effect of caloric supplementation on weight in underweight adults and children with growth retardation. Also, robust designs for efficacy studies are needed to help clarify whether multi-nutrient combinations (“cocktails”) would be more effective than single nutrients. Given the high inter-individual variability in clinical manifestations and nutritional status, supplementation studies should be designed using an informed approach that avoids problems of placebo effects and the high probability of false positive results (Type 1 (alpha) error).
  • Clarifying whether individually targeted nutritional assessment followed by nutritional intervention has the capacity to mitigate disease severity, complications, and quality of life in patients with SCD and thalassemia, and whether improved or normalized micronutrient and protein status has the capacity to also improve nitrogen and energy balance for growth, maintenance, repair, and physical activity.
  • Defining elements of cardiovascular disease risk for individuals with sickle cell disease. Sickle cell disease is associated with a variety of cardiopulmonary disorders and their sequelae, including pulmonary hypertension, left or right ventricular dysfunction, arrhythmias, and sudden death. Patients with sickle cell disease are prone to vaso-occlusive disease and have impaired endothelial vasodilator function and altered bioavailability and function of endothelium-derived nitric oxide. Possible mechanisms of endothelial dysfunction have been proposed, including increased oxidative stress and increased circulating cell free hemoglobin that may bind and inactivate nitric oxide. In addition, sickle RBCs may adhere more readily to the endothelial surface. Non-invasive tools for assessment of endothelial health include ultrasound evaluation of the brachial artery endothelial function (hyperemic response) and intra-arterial infusions and forearm venous occlusion plethysmography (measurement of vessel resistance) as well as newer methods such as fingertip peripheral arterial tonometry (PAT, an assessment of vascular stiffness). Circulating measures reflecting endothelial dysfunction (such as cell types and molecular biomarkers) also may have predictive value in assessing cardiovascular risk.
  • Understanding specific diet-related requirements and treatments for thalassemia patients. Issues needing research include: energy balance considerations for optimal growth, development and activity; absorption and utilization of individual nutrients; risks and benefits of vitamin D supplementation at doses up to and including the pharmacologic range, especially in chronically transfused patients; effects of deferoxamine and other chelating agents on static and functional markers of zinc, copper, and selenium status; effects of adequate replacement of micronutrients on chelator efficacy; and effects of specific nutrients on immune function, bone health, and oxidative stress.
  • Understanding physical activity and exercise physiology issues in hemoglobinopathies patients. Exercise capacity in most SCD patients generally is reduced due to cardiovascular, pulmonary, or musculo-skeletal limitations. Decreased exercise capacity in thalassemias stems from anemia in children, deconditioning, and poor myocyte oxygen extraction, and in adults from cardiac siderosis, pulmonary hypertension, diastolic and/or systolic dysfunction, or heart failure. Exercise capacity may not predictably improve with medical treatments (such as transfusions or hydroxyurea) or, in contrast to healthy individuals, with physical training. The energy costs and fluid balance demands of physical activity are not well understood for this population. Also, the relationship of measures such as hand-grip strength and free living physical activity as predictors of clinical status and long-term health outcomes needs to be clarified. Patients, families, and educators need guidance on fluid needs, the effects of ambient temperatures, pace and intensity of activity, and other factors that will facilitate participation in physical activity and sports.
  • Developing best practices for the assessment of the behavioral and social dimensions of nutrition and diet in hemoglobinopathies patient populations. For example, information is needed on dietary practices and food-ways of specific ethnic subpopulations (e.g., African Americans in Chicago, Dominicans in New York) as these may affect nutritional status and also determine best practices for dietary counseling. Quality-of-life dimensions of diet and issues of self-care (such as meal preparation and use of herbal supplements) potentially can be assessed with the Patient Related Outcomes Measurement Information System (PROMIS) toolbox (http://www.nihpromis.org/default). Food insecurity, which occurs when economic constraints may prevent access to food, is a particular problem for individuals with chronic disease and for low income individuals, and can lead to nutritional adequacy and anxiety.
  • Characterizing nutritional status, dietary practices, exercise physiology, and cardiovascular physiology in individuals with sickle cell trait (Hb AS). The medical history should include information on co-morbid conditions of interest, including deep vein thrombosis and renal disease.

Population Science: Nutritional Epidemiology and Surveys

Leveraging the potential for nutrition- and diet-related data collection on hemoglobinopathy phenotypes in ongoing national surveys and other national public health and nutrition programs
Established surveys, data systems, and public health or income support programs can be considered as resources for epidemiology studies, including data mining, sample analysis, or questionnaires to provide information on different patient subpopulations of interest, which include:

  • Infants identified through newborn screening and diagnosed with sickle cell anemia and hemoglobin SC disease in a given year or years;
  • Children and adults with sickle cell anemia on hydroxyurea therapy;
  • Individuals with transfusion-dependent thalassemia;
  • Immigrant children and adults or adults born before newborn screening was started (i.e., late diagnoses where numbers of patients may be relatively small but the big picture of health care impact in terms of suffering and cost is large); and
  • Persons with sickle cell trait or other carrier conditions.

Information from population-based estimates is needed to understand the prevalence and geographic distribution of these populations. There also is a need for statistically sound information on medical care utilization and complications rates in sickle cell disease and thalassemia patient populations, including disease severity, co-morbidities, and chronic disease complications. These data needs are compatible with those identified in the Healthy People 2020 Objectives for Blood Disorders and Blood Safety (Hemoglobinopathies) (see http://www.healthypeople.gov/2020/topicsobjectives2020/objectiveslist.aspx?topicId=4).

When available, registries enable the identification of cohorts from whom data will be collected longitudinally. Registry data can be used to examine patient outcomes and can provide data to compare different therapeutic modalities under different patterns of health care. In theory, a statistically representative sample of patients in a registry could have biospecimens stored in a repository for nutritional and metabolic biomarkers, genotype, phenotype, and genomic studies designed to increase knowledge about disease phenotypes and possible genetic influences on health outcomes and response to therapy. Genetic studies or collection and banking of samples, such as immortalized white blood cells, may require additional approvals and human subjects protection reviews for safety or ethical issues.

It might be possible to add questions to existing data collection activities, such as surveys or public health monitoring systems (see below), to determine whether respondents have a phenotype of interest (SCD, sickle cell trait, thalassemia, etc.). Another alternative is to connect various systems (case identification and screening, health and social services, etc.) to provide longitudinal cohort data, perhaps at the state level. However, a major barrier is the low prevalence of these conditions, which makes the assessment challenging as there would be a low yield of subjects for the effort and cost invested. Suitable privacy and safety protections are a critical part of conducting such research.
For rare diseases such as hemoglobinopathies, case-control and nested case-control designs could prove an efficient research model, but may also be appropriate for more common diseases. The two types of studies designs have different structure based on the original source of the cases. In case-control studies, cases and controls are sampled from a source population with unknown size. Case-control studies work best when they draw upon available case ascertainment systems, such as a population-based cancer registry, hospital based surveillance systems, or mandated disease reporting systems (such as newborn screening for genetic diseases).

In nested case-control studies, cases and controls are drawn from (i.e., “nested') an existing well-defined and already characterized source population or cohort with known sample size. Compared with case-control designs, nested case-control designs have several advantages. First, the possibility of recall bias is eliminated, since data on exposure are obtained before disease develops; exposure data are more likely to represent the pre-illness state, since they are obtained years before clinical illness is diagnosed. Also, the prior characterization of the cohort may include stored data and biological specimens, which can be re-analyzed for diagnostic and research purposes. Costs are reduced compared to those of a prospective study, since the laboratory tests need to be done only on specimens from subjects who are later chosen as cases or as controls. A limitation of nested case-control designs is that it may be difficult to assign causality due to the time lag between cohort enrollment and outcome events, or because the available data or samples do not allow assessment of additional variables or confounders. Another disadvantage is that the selected controls may not be fully representative of the underlying cohort or population due to death or other loss to follow up.

The economic burden experience of living with a hemoglobinopathy could be studied by using data from surveys of health care providers, health plans, and medical expenditures, as well as data sets provided by the Centers for Medicaid and Medicare Services (CMS; http://www.cms.gov/Research-Statistics-Data-and-Systems/Research-Statistics-Data-and-Systems.html), and Medical Expenditure Panel Survey (MEPS), which draw its samples from the National Health Interview Survey (NHIS) (see below), and tools such as PROMIS (see below). Many hemoglobinopathies patients, however, are not enrolled in health plans and have poor access to care, which will affect which data sources (such as health plans) can be considered for research purposes. Furthermore, food insecurity, an identified concern in chronic disease populations as well as low income individuals, can have major consequences for nutrient status, self-care, quality of life, and psychological stress.

Participation in U.S. Department of Agriculture (USDA) food support programs (see below) is another important dimension of data for understanding the economic situation of hemoglobinopathies patients. The Centers for Disease Control and Prevention (CDC) (http://www.cdc.gov/) oversees an array of nutrition-related surveys and public health surveillance programs that could provide reference values for populations with hemoglobinopathies.

  • The CDC National Health and Nutrition Examination Survey (NHANES) (http://www.cdc.gov/nchs/nhanes.htm/) is the only national survey that gathers information on nutrition status and supplement use in addition to information on health conditions acquired through direct physical examination, in-person interviews, and laboratory assays of biological specimens. NHANES began in the early 1960’s and has had multiple cycles and sub-studies, with some variation in the sampling design and measurements. NHANES is particularly important for determining the prevalence of conditions and risk factors in the U.S. population and for monitoring changes in nutritional status over time (http://www.cdc.gov/nchs/nhanes/about_nhanes.htm). The physical examination component (anthropometry, bone density through DEXA scans, etc.) has the advantage of controlling for confounding and bias that might occur in self-reported data. NHANES is a good source of information on population reference values, but generally does not yield sufficient numbers for the study of rare conditions such as hemoglobinopathies.
  • The CDC National Center on Birth Defects and Developmental Disabilities (http://www.cdc.gov/ncbddd/index.html) has overseen two programs in hemoglobinopathies monitoring: the Thalassemia Data Collection Project (ongoing) and Registry and Surveillance System for Hemoglobinopathies (RuSH) (completed) (http://www.cdc.gov/ncbddd/hemoglobinopathies/index.html).
  • The CDC National Health Interview Survey (NHIS) http://www.cdc.gov/nchs/nhis.htm is a large public health monitoring survey with multiple components and sub-samples. For example, through Medical Expenditure Panel Survey (MEPS) subsampling, NHIS collects information on economics data, such as out-of-pocket costs, expenditures, and reimbursement. By adding questions to the NHIS about sickle cell disease and other hemoglobinopathies, it might be possible to estimate how many have been diagnosed with SCD or thalassemias and to determine whether this is an adequate sample size for data analyses. This would be of particular interest if the NHIS adds a Complementary and Alternative Medicine supplement to future survey cycles.
  • The CDC Pediatric and Pregnancy Nutrition Surveillance System (PedNSS) http://www.cdc.gov/pednss/) collects data on specific health indicators for infants, children, and mothers who go to public health clinics for routine care, nutrition education, and supplemental food assistance. Anemia, breastfeeding status, low and high birth weight, short stature, underweight, overweight, obesity, TV/video viewing, and household smoking are key indicators of nutritional and health status collected by the PedNSS (http://www.cdc.gov/pednss/what_is/pednss_health_indicators.htm). It might be possible to identify individuals or groups of individuals with hemoglobinopathies among the PedNESS participants and to evaluate their health indicators.

The National Children's Study (NCS) is designed to examine the effects of the environment (broadly defined to include factors such as air, water, diet, sound, family dynamics, community and cultural influences, and genetics) on the growth, development, and health of children across the United States, following them from before birth until age 21 years (http://www.nationalchildrensstudy.gov/Pages/default.aspx). The NCS could be a suitable source of reference or comparison data, but for rare conditions such as hemoglobinopathies the likely sample size will be too small for adequate statistical power, unless combined with data from other birth cohorts.

State-level Newborn Screening (NBS) programs conducted by all states and the District of Columbia (http://mchb.hrsa.gov/programs/newbornscreening/index.html) test for sickle cell disease and some states test for thalassemias. State databases that include, or can be linked to, confirmed diagnoses may be a resource when combined with other data.

The USDA Food and Nutrition Service (http://www.fns.usda.gov/fns/) provides nutrition and food assistance to low income families through programs such as the Supplemental Nutrition Assistance Program (SNAP, formerly called Food Stamps) and the Women, Infants, and Children Program (WIC) (http://www.fns.usda.gov/wic/). There is a connection between WIC enrollment and sickle cell disease experience, in that a high fraction of African-American mothers and children are enrolled in this program as well as other low-income groups, such as immigrants. In some states it might be possible to follow babies identified with hemoglobinopathies based on newborn screening for 5 years by analyzing associated WIC data. (Note: a 5-year time frame is necessary to obtain adequate numbers for satisfactory statistical power.) This approach could provide valuable information on the nutritional intake of infants and young children with sickle cell disease.

The NIH Patient Related Outcomes Measurement Information System (PROMIS) for evaluating patient-reported health outcomes might be a good tool for understanding diet as a route of self-care. Pain management, stress, and quality of life assessment are important components of the PROMIS toolbox. Adult and child versions of the tools are available
(see: http://www.nihpromis.org/default).

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Working Group Members

  • Thomas D. Coates, MD, Children’s Hospital, Los Angeles CA (Co-Chair)
  • Virginia A. Stallings, MD, Children’s Hospital, Philadelphia PA (Co-Chair)
  • Gina Cioffi, JD, Cooley’s Anemia Foundation, New York NY
  • Rebecca Costello, PhD, Office of Dietary Supplements, NIH
  • Kathleen Durst, MA, LMSW, Cooley’s Anemia Foundation, New York NY
  • Johanna Dwyer, DSc, RD, Office of Dietary Supplements, NIH
  • Ellen Fung, Ph.D., RD, CCD, Children’s Hospital & Research Center, San Francisco CA
  • Althea M. Grant, PhD, Centers for Disease Control and Prevention, Atlanta GA
  • Ralph Green, MD, PhD, FRCPath, University of California, Davis CA
  • Violanda Grigorescu, MD, MSPH, Centers for Disease Control and Prevention, Atlanta GA (formerly of Michigan Department of Community Health, Lansing MI)
  • Lanetta Jordan, MD, MPH, University of Miami, Miami FL (formerly of Memorial Healthcare System), Hollywood FL
  • Eric U. Kirkwood, BS, Uriel Owens Chapter, Sickle Cell Disease Association, Kansas City KA
  • Barbara Laraia, PhD, MPH, RD, University of California, San Francisco CA
  • Robert Liem, MD, Children’s Hospital of Chicago, Chicago IL
  • Jean Ann Olds, MS, RD, The Children’s Hospital, Anschutz Medical Campus, Denver CO
  • Kathryn Porter, MD, MS, National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville MD
  • Thomas Ryan, Ph.D., University of Alabama, Birmingham AL
  • William P. Tonkins, Jr., PhD, National Institute of Arthritis and Musculoskeletal Diseases, NIH
  • Joseph Vita, MD, Boston University School of Medicine
  • Steven Zeisel, MD, PhD, University of North Carolina, Chapel Hill NC

Planning Committee

  • Thomas D. Coates, MD, Children’s Hospital, Los Angeles CA (Co-Chair)
  • Virginia Stallings, MD, Children’s Hospital, Philadelphia PA (Co-Chair)
  • Abby Ershow, ScD, Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, NIH (Project Officer)
  • Rebecca Costello, PhD, RD, Office of Dietary Supplements, NIH (Project Officer)
  • Ellen M. Werner, PhD, Division of Blood and Disease Resources, National Heart, Lung, and Blood Institute, NIH (Project Officer)
  • Johanna Dwyer, DSc, RD, Office of Dietary Supplements, NIH
  • Althea M. Grant, PhD, Centers for Disease Control and Prevention, Atlanta GA
  • Margaret McDowell, PhD, RD, Division of Nutrition Research Coordination, National Institute of Diabetes and Digestive and Kidney Diseases, NIH
  • Susan Pilch, PhD, Clinical Center Library, Office of Research Services, NIH

Appendix
Meeting Agenda (with links to abstracts and biosketches)

Acknowledgements
The Planning Committee gratefully acknowledges the assistance of the following NHLBI staff in the management of this workshop and preparation of this report: Christine Wiser Chung, Nina Hall, Maya Harris, Madison Scott, Wanda Ware, and Della Claiborne.

Last Updated: September 12, 2013

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