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U.S. Environmental Protection Agency
Office of Research and Development
National Center for Environmental Research
Science to Achieve Results (STAR) Program
CLOSED - FOR REFERENCES PURPOSES ONLY
Epidemiologic Research on Health Effects of Long-Term Exposure to Ambient Particulate Matter and Other Air Pollutants
Opening Date: February 21, 2003
Closing Date: July 24, 2003
Summary of Program Requirements
Specific Areas of Interest
Standard Instructions for Submitting an Application
Get Standard STAR Forms and Instructions
View NCER Research Capsules (http://www.epa.gov/ncer/publications/topical/)
View research awarded under previous solicitations (http://www.epa.gov/ncer/rfa/archive/grants/)
Epidemiologic Research on Health Effects of Long-Term Exposure to Ambient Particulate Matter and Other Air Pollutants
Synopsis of Program
The U.S. Environmental Protection Agency (EPA), as part of its Science to Achieve Results (STAR) program, is seeking applications for a prospective observational study of cardiovascular disease initiation and progression associated with long-term exposure to ambient particulate matter and other air pollutants in a population-based sample. Particulate matter (PM) has been linked to serious respiratory and cardiovascular disease. Important health outcomes associated with exposure to ambient particulate matter include: premature mortality, aggravation of respiratory and heart disease (as indicated by increased hospital admissions and emergency room visits, school absences, work loss days, and restricted activity days), aggravated asthma, acute respiratory symptoms, chronic bronchitis, decreased lung function, and increased risk of myocardial infarction. This request for applications (RFA) invites applications for prospective epidemiology studies using validated measures of subclinical disease to study the natural history of cardiovascular disease associated with long-term exposure to ambient particulate matter and co-pollutants.
Barbara Glenn; Phone: 202-564-6913; email: email@example.com
Gail Robarge; Phone: 202-564-8301; email: firstname.lastname@example.org
Stacey Katz; Phone: 202-564-8201; email: email@example.com
Applicable Catalog of Federal Domestic Assistance (CFDA) Number(s): 66.509
Academic and not-for-profit institutions located in the U.S., and state or local governments are eligible to apply for assistance under this program.
Anticipated Type of Award: Grant or Cooperative Agreement
Estimated Number of Awards: 1
After submission of proposals and completion of the peer review process, EPA officials will determine if a grant or cooperative agreement funding mechanism best suits the proposed project. Names of potential EPA collaborators should not be provided in the proposal.
Anticipated Funding Amount: A total of $30 million including direct and indirect costs over a ten-year project period.
Potential Funding per Grant per Year: Approximately $3 - 4 million per year for the first five years and $1-2 million per year for the second five years.
The sorting code for applications submitted in response to this solicitation is 2003-STAR-F1.
Letter of Intent Due Date(s): None
Application Proposal Due Date(s): July 24, 2003
Epidemiologic Studies of the Health Effects of Long-Term PM Exposures
Long-term exposure to ambient airborne particulate matter is associated with increased mortality, largely due to respiratory (including lung cancer) and cardiovascular causes (Dockery et al. 1993; Pope et al. 1995; Abbey et al. 1999; McDonnell et al. 2000; Pope et al. 2002). The mortality risk is most strongly related to ambient concentrations of fine particles less than 2.5 µm in diameter, and sulfates. In addition to mortality, particulate matter with aerodynamic diameter less than 10 µm, between 2.5 to 10 µm, or less than 2.5 µm is associated with a reduction in lung function development among school-age children (Jedrychowski et al. 1999; Gauderman et al. 2000; Gauderman et al. 2002). The health effects also are associated with other air pollutants including nitrogen dioxide, ozone, and inorganic acid vapor. The identification of those health endpoints that are associated with specific particulate matter constituents and other pollutant types is a current EPA research priority.
Since the initial studies were published, more sophisticated air pollution monitoring technologies were developed and federal and local monitoring programs were begun to measure fine particulate matter levels and particle species (at some sites) over a broader geographic area. New prospective studies are needed that incorporate the newer PM concentration measurements and technologies to study more diverse study populations. These studies will need to directly address design and analytical issues such as: (1) the collection of data on individual level risk factors and personal exposure factors, (2) adjustment for simultaneous exposure to gaseous and other co-pollutants, and (3) the spatial correlation of mortality and pollution levels.
Subclinical Changes Associated with Particulate Matter Exposure
In recent years, many time series and panel studies have linked increased numbers of hospitalizations for cardiovascular events, including myocardial infarction, with air pollution levels on the days preceding the event (Burnett et al. 1995; Schwartz 1999). While they primarily provide strong evidence of effects from an acute exposure, some studies also linked mortality and hospitalization for cardiopulmonary and cardiovascular disease with ambient particle levels measured 5 - 6 weeks earlier (Braga et al. 2001; Zanobetti et al. 2002). Researchers have begun to investigate physiological changes that may mediate the observed relation with cardiovascular effects. Acute effects including reduced heart rate variability, increased heart rate, and defibrillator discharges due to ventricular arrhythmias in patients with implanted cardioverter defibrillators have been associated with daily changes in particle levels (Liao et al. 1999; Pope et al. 1999; Gold et al. 2000; Peters et al. 2000). These studies suggest that an effect on the autonomic control of the heart may play a role. Brook et al. (2002) reported decreased brachial artery diameter associated with controlled human exposures to a mixture of concentrated ambient particles (CAP) and ozone, suggestive of systemic effects (Brook et al. 2002). Other investigations have explored the effect of daily ambient air pollution levels on indicators of pulmonary and circulatory inflammation as risk factors for coronary disease and mortality including plasma viscosity, plasma fibrinogen and peripheral neutrophils (Seaton et al. 1995; Peters et al. 1997; Salvi et al. 1999; Seaton et al. 1999; Ghio et al. 2000). These studies suggest that critical events such as myocardial infarction or arrhythmia may be mediated by inflammatory or oxidative damage, either through direct effects in the lung, or via systemic changes that alter endothelial and cardiac function. Individuals with existing cardiovascular or respiratory disease may be more susceptible to the events triggered by recent particulate matter exposure.
Whether or not long-term particle exposure plays a role in the initiation or progression of chronic conditions such as atherosclerosis, diabetes, chronic obstructive pulmonary disease (COPD), chronic bronchitis, and asthma is a critical research question. No studies have evaluated long-term exposure to ambient levels of particulate matter in relation to measures of the progression of chronic disease, such as coronary artery disease or atherosclerosis. Two validated, reproducible measures that have been used by other researchers to follow the subclinical progression of atherosclerosis are measurement of coronary calcification by computed tomography and ultrasound measurement of the common carotid artery. These measures predict the risk of adverse clinical events and are associated with well-established risk factors for cardiovascular disease. Prospective studies using outcome measures such as these would significantly advance our understanding of the contribution of ambient air pollution to the development of chronic disease.
In addition, there is little current understanding of whether individual attributes such as age, the presence of disease or risk factors for disease, residential location (inner-city, suburban, rural), education level, or race/ethnicity, place individuals at higher risk (effect modifiers). This research will be important to identify populations that are particularly susceptible to the adverse effects of long-term exposure to ambient particulate matter.
Characterization of Particulate Matter
Particulate matter represents a broad class of chemically and physically diverse substances. Particles can be described by size, formation mechanism, origin, chemical composition, atmospheric behavior and method of measurement. The concentration of particles in the air varies across space and time, and is related to the source of the particles and the transformations that occur in the atmosphere. Particulate matter can be classified into discrete size categories spanning several orders of magnitude, with inhalable particles falling into the following general size fractions: PM10 (equal to and less than 10 microns in aerodynamic diameter), PM10-2.5 (greater than 2.5 microns but equal to or less than 10 microns), PM2.5 (2.5 microns or less), and ultrafine (less than 0.1 microns).
U.S. EPA Ambient Air Quality Monitoring Program
The EPA's ambient air quality monitoring program is carried out by State and local agencies and consists of three major categories of monitoring stations, State and Local Air Monitoring Stations (SLAMS), National Air Monitoring Stations (NAMS), and Special Purpose Monitoring Stations (SPMS), that measure the criteria pollutants (http://www.epa.gov/oar/oaqps/qa/monprog.html). Additionally, a fourth category of monitoring station, the Photochemical Assessment Monitoring Stations (PAMS), which measures ozone precursors (approximately 60 volatile hydrocarbons and carbonyl) has been required by the 1990 Amendments to the Clean Air Act. Direct measurements of PM2.5 were begun in 1999 at some locations. More detailed atmospheric measurements of particulate matter constituents and co-pollutants were taken at nine Supersites between 2000 and 2002. In 2001, the Supersite program was incorporated into a PM2.5 Speciation Monitoring Network. The network is composed of monitors that characterize the physical and chemical properties of particles in the PM2.5 size fraction.
The EPA is restructuring its routine ambient air pollution monitoring program to accommodate national and local needs, improve information flow to the public, and incorporate new technologies and new pollutant measurements. The Agency intends to upgrade many of the PM mass monitors to conduct continuous monitoring of PM2.5, carbon, sulfates, and nitrates. Information about the proposed strategy, the "National Ambient Air Monitoring Strategy," is available at http://www.epa.gov/ttn/amtic/monitor.html. The Agency anticipates that the data collected as a result of the air monitoring program will be used in prospective epidemiology studies, although additional study specific exposure measurements may be required to address exposure indices involving particle counts and certain toxic species.
Ambient monitoring data for Trends from the EPA's PM2.5 Chemical Speciation Trends Network is usually referred to as 'Speciated Trends Network (or STN).' The PM2.5 STN was established by regulation and is a companion network to the mass-based Federal Reference Method (FRM) network implemented in support of the PM2.5 NAAQS. EPA established the STN network to provide nationally consistent speciated PM2.5 data for the assessment of trends at representative sites in urban areas across the country. As part of a routine monitoring program, the STN quantifies mass concentrations and PM2.5 constituents, including numerous trace elements, ions (sulfate, nitrate, sodium, potassium, ammonium), elemental carbon, and organic carbon. The STN began operation in late 1999, and there are a total of 54 STN sites. As of this writing, data in the STN goes through approximately October 2002 and there are at least a year's worth of data for about 36 of the 54 STN sites. To assist in the development of proposals in response to this RFA, a spreadsheet titled, "PM2.5 urban speciation monitors," can be found on the EPA ORD/NCER website at the following address: http://www.epa.gov/ncer/rfa/current/2003_pm_epi-monitors.html. The spreadsheet presents a subset of the EPA urban chemical speciation data contained in the Air Quality System and represents annual average concentration data for the time period March 2001 to February 2002. Two accompanying files can be found that define the variables found in the spreadsheet, as well as in the Air Quality System.
Measurement of Ambient Exposure and Total Personal Exposure to Particulate Matter
Average annual particulate matter concentrations do not vary significantly within a geographic region unless there have been significant changes in source characteristics (e.g., highway construction, power plant operation, industrial process changes, forest fires). Therefore, to achieve the necessary variability in annual ambient PM concentrations, epidemiology studies of long-term particulate matter exposure must follow populations residing in multiple locations. Longitudinal studies generally have used available data on concentrations of particulate matter (including total suspended particles (TSP), PM15, PM10, PM2.5, sulfates) and gaseous pollutants (ozone, SO2, NOx, etc.) collected at existing regional ambient air monitoring stations or, in some cases, at special monitoring stations established as part of the study. Mortality has been analyzed in relation to average annual pollutant concentration for periods of time comparable across all study sites. The measurement error associated with this exposure estimate depends on the degree to which pollutant concentrations proximal to centrally located monitors are correlated with the actual exposure levels experienced by people living in a region. Recently, researchers have begun to use more refined estimates of long-term ambient concentrations that characterize the contribution by regional, urban, and local sources (Hoek et al. 2001).
Several individual-level factors may alter a person's exposure to ambient air pollution including residence and work location, proximity to local particulate matter sources such as power plants and heavily trafficked roadways, activity patterns, housing air exchange rates, and use of air conditioning. Finally, indoor particle sources, such as gas stoves, wood burning stoves, and cigarette smoke may contribute significantly to total personal exposure to certain particulate matter components. The relative importance of individual-level factors and indoor sources in relation to acute or chronic health effects may vary depending on the time frame of interest (days, weeks, years) and geographically. Longitudinal studies are needed that collect information on additional factors that alter an individual's exposure to ambient particulate matter, as well as indoor sources.
Studies that identify and test hypotheses concerning alternative exposure metrics in addition to particle size, such as particle counts and chemical composition, will extend our understanding of the toxicity of particulate matter constituents. Further, exposure indices are needed to evaluate relevant temporal patterns of exposure, including cumulative measures. The relevant exposure period for the retrospective assessment of particulate matter exposures is not known. However, studies of smoking cessation indicate that significant health benefits (extension of life and decreased risk of coronary heart disease) occur within the first 5 to 10 years (Kawachi et al. 1994; Taylor et al. 2002).
Analyzing the Relative Importance of PM Size Classes and Gaseous Co-Pollutants
It is difficult to isolate the unique effects of any single constituent in a complex mixture. Multipollutant analytical models are complicated by correlation among the pollutant variables. Adjustment for the effects of co-pollutants is important, however interpretation of the risk estimates for any single pollutant is difficult because individual pollutant concentrations can be correlated. Another potential source of confounding in epidemiology studies of populations located in several different geographic regions is unmeasured risk factors that are spatially correlated. Inadequate control for spatial autocorrelation and clustering can lead to an underestimate of the uncertainty as well as possible bias in the size of the estimated risk (Burnett et al. 2001).
In a recent evaluation of research concerning particulate matter exposure and health effects, the National Research Council highlighted a critical need for additional studies of the long-term health effects of particulate matter (National Research Council 2001). The NRC recommended that studies should evaluate alternative particulate matter exposure metrics, the effect of particles in combination with gaseous co-pollutants, and effects in potentially susceptible groups.
Prospective epidemiology studies are needed to extend the knowledge gained from previous studies that identified an increased risk of cardiopulmonary and cardiovascular mortality and hospitalizations in older individuals, as well as decreased development of lung function among school-age children. The U.S. EPA is soliciting proposals to recruit a new adult cohort to be followed prospectively to study indicators of the progression of cardiovascular disease and cause-specific hospital admissions and mortality. The research effort will have the objectives described below.
A multi-site, prospective, population-based observational study of adults designed to determine the long-term effects of PM constituents and co-pollutants on the natural history of cardiovascular disease, including indicators of sub-clinical disease, clinical disease incidence, mortality and the assessment of physiological parameters indicative of the progression of disease. Study proposals should address all of the following questions:
- Does long-term exposure to ambient particulate matter increase the risk of cardiovascular disease incidence or progression?
- Is annual change in the value of specific physiologic parameters, or increased incidence of intermediate subclinical and clinical outcomes associated with long-term exposure to particulate matter?
- Are these adverse health endpoints differentially associated with specific chemical constituents, size fractions, or sources of ambient particulate matter?
- What are the most relevant methodologies and exposure metrics for estimating the adverse health effects of long-term exposure to ambient particulate matter?
The EPA is particularly interested in proposals that specifically address all of the elements described below.
- Health endpoints. The EPA is interested in proposals having
a primary focus on the evaluation of the annual change in indicators
of cardiovascular disease progression in adults. Other outcome measures,
including lung function decline, incidence of hospitalizations, or mortality,
are of secondary interest. Study protocols that include repeated measurements
of validated, state-of-the-art, noninvasive subclinical health outcomes
are desired. Repeated measures should be of sufficient precision and
sensitivity to demonstrate progression of cardiovascular disease in
individuals. Outcomes that are objective predictors of clinically relevant
health endpoints and that are associated with well-established risk
factors for the clinical endpoints are of highest interest.
A study design with sufficient power to detect an association between long-term exposure to ambient particulate matter and a biologically relevant change in the physiologic variables under study over a three to four year observation period is desired. The Agency does not expect that the studies will have adequate power to detect an association of exposure measures with the incidence of clinically diagnosed adverse events (e.g., hospitalizations) over this same time period. However, proposals that are sufficiently powered to detect an association between long-term exposure to ambient particulate matter and the incidence of clinically recognized cardiovascular or respiratory disease, over a ten-year time period are preferred.
- Confounding. Study designs or statistical strategies to control
for potential confounding by other major determinants of cardiovascular
disease, such as smoking, diet, exercise, and socioeconomic status,
are preferred. If general unrestricted study populations are selected,
they should be large and diverse enough to permit careful adjustment
for individual-level characteristics that may confound the relation
between health endpoints and pollution levels. Questionnaire assessment
of certain potential confounders, such as smoking status, should be
validated by the collection of biologic samples in a subset of individuals.
- Effect modification. The Agency is interested in proposals
with study populations that are large and diverse enough to examine
individual-level characteristics that have been shown to modify the
relation between health endpoints and air pollutants. Research objectives
that include hypotheses to address individual susceptibility are desired.
- Exposure gradients. Study populations with an adequate range
of average annual ambient concentrations of airborne particulate matter
are preferred. The EPA is interested in both regional (e.g., transported
sulfates and nitrates, gradients related to specific home heating fuels
such as residual fuel oil and wood) and local (e.g., intra-urban concentration
gradients from mobile sources) gradients in ambient concentrations.
The Agency anticipates that individuals from multiple geographic regions
will be selected to meet this interest. The research narrative should
describe why study locations were selected and the extent to which the
use of federal, state, and local monitoring systems and data was considered.
- PM constituents and co-pollutants. In addition to inhalable
particulate matter (PM10), the EPA prefers studies that consider other
specific chemical constituents and size fractions of ambient particulate
matter and co-pollutants. The Agency is interested in the study of fine
particles (PM2.5) as well as alternative exposure metrics for PM including
the chemical composition of particles and source apportionment. Various
temporal patterns of exposure should be considered, including measures
of cumulative exposure.
- Exposure misclassification. Proposals should include the use
of Geographic Information Systems (GIS) or other methods to estimate
ambient concentration at each subject's residence using pollutant measurements
taken at central monitoring sites. Successful proposals will include
the identification and analysis of factors that affect personal exposure
to ambient air pollution. These factors may include local, personal,
or household factors. Validation studies using indoor or personal monitors
should not comprise more than 10 to 20 percent of the project's total
- Analytic issues. The Agency anticipates that the use or development
of sophisticated analytical tools will be necessary to disentangle the
individual contribution of particulate matter components and co-pollutants,
account for spatial clustering and autocorrelation, and address other
- Investigator expertise. Specific areas of desired multidisciplinary
expertise include epidemiology with experience in longitudinal study
design, data collection, and statistical analysis; clinical aspects
of cardiovascular disease; quality assurance responsibilities for laboratory,
clinical and epidemiologic measurements, particularly assessing and
controlling for measurement error; biostatistics; and air quality monitoring
and exposure assessment.
- Study management. The proposal should present a plan (four to five pages in length) for the management and support of the activities of an administrative core and steering committee. (see below for details).
Study Administration and Oversight
The Agency expects that the study design will involve the separation of study personnel and data collection geographically and over time. Therefore, special consideration will be required in the management of data collection, storage, and analysis to assure that study protocols are carried out in the same manner for each study subject. This should be accomplished through an administrative core.
Responsibilities of the administrative core unit should include oversight and coordination of the study's components including the development and implementation of the study protocol in accordance with the study timelines, management of subcontracts, training of staff, development and maintenance of databases, development and direction of the quality assurance program, the conduct of statistical analyses, facilitation of communication within the study and with the EPA project officer, and performance of other administrative duties.
A steering committee for the administrative core should be formed to review and approve the study protocol, the training manuals, the database structure, and the quality assurance plan. The steering committee should monitor the progress of the study, and review and approve proposals for manuscripts. Collaborators from each study site, the Principal Investigator for the study, the EPA Project Officer, an EPA intramural researcher and two independent researchers from the academic and/or government research community may participate on the steering committee.
The proposal should present a plan (four to five pages in length) for the administration and support of the activities of the administrative core and the steering committee. The plan should include the procedures for and frequency of communication (teleconference and on-site meetings) and coordination, as well as the mechanism for decision-making by the steering committee. The plan should also include a diagram illustrating the administrative structure for the study.
Data Confidentiality and Data Sharing
The proposal must include a plan to make available all non-identifiable statistical data (including primary and secondary/existing data) from observations, analyses, or model development under the assistance awarded as a result of this RFA in a format and with documentation such that other qualified researchers in the scientific community can use these materials. The data must be made available to the project officer without restriction and be accompanied by comprehensive metadata documentation adequate for specialists and non-specialists alike to be able to understand how and where the data were obtained and to evaluate the quality of the data.
Applicants who develop databases containing proprietary or restricted information shall provide a strategy, not to exceed two pages, to make the data widely available, while protecting privacy or property rights. These pages are in addition to the 35 pages permitted for the project narrative.
Project Period and Research Plan (two five-year phases)
The project period for this solicitation shall be a total of ten years with two study phases. The research plan should describe in detail the study design to address research objectives for the first five-year phase. A less detailed plan for the second five-year phase (follow-up of cause-specific hospital admissions and mortality) may be presented in this research proposal. At the end of the fourth year following the award, the recipient will be required to submit a detailed proposal for the second phase. The proposal for phase two will be required to contain a description of the study's results and conclusions obtained to that point in time and a detailed study design and protocol for the remainder of the project period. The funding for the last five years will be contingent on initial progress made in the study, the merit of the proposed work as determined by external peer reviewers, the availability of funds, and the priorities of the Agency.
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It is anticipated that a total of approximately $30 million will be awarded, depending on the availability of funds. EPA seeks the most cost-effective proposals that utilize funding of up to $3 - 4 million per year for the first five years and $1-2 million per year for the second five years. EPA requires proposals that address all of the research objectives while staying within the maximum EPA funding contribution of $30 million, including direct and indirect costs. Requests for EPA funding exceeding $30 million will not be considered.
Academic and not-for-profit institutions located in the U.S., and state or local governments, are eligible under all existing authorizations. Profit-making firms are not eligible to receive grants from EPA under this program. Federal agencies and national laboratories funded by federal agencies (Federally-funded Research and Development Centers, FFRDCs) may not apply.
Federal employees are not eligible to serve in a principal leadership role on a grant. FFRDC employees may cooperate or collaborate with eligible applicants within the limits imposed by applicable legislation and regulations. They may participate in planning, conducting, and analyzing the research directed by the principal investigator, but may not direct projects on behalf of the applicant organization or principal investigator. The principal investigator's institution may provide funds through its grant from EPA to a FFRDC for research personnel, supplies, equipment, and other expenses directly related to the research. However, salaries for permanent FFRDC employees may not be provided through this mechanism.
Federal employees may not receive salaries or in other ways augment their agency's appropriations through grants made by this program. However, federal employees may interact with grantees so long as their involvement is not essential to achieving the basic goals of the grant.1 The principal investigator's institution may also enter into an agreement with a federal agency to purchase or utilize unique supplies or services unavailable in the private sector. Examples are purchase of satellite data, census data tapes, chemical reference standards, analyses, or use of instrumentation or other facilities not available elsewhere, etc. A written justification for federal involvement must be included in the application, along with an assurance from the federal agency involved which commits it to supply the specified service.
1EPA encourages interaction between its own laboratory scientists and grant principal investigators for the sole purpose of exchanging information in research areas of common interest that may add value to their respective research activities. However, this interaction must be incidental to achieving the goals of the research under a grant. Interaction that is "incidental" is not reflected in a research proposal and involves no resource commitments.
Potential applicants who are uncertain of their eligibility should contact Jack Puzak in NCER, phone (202) 564-6825, Email: firstname.lastname@example.org.
A set of special instructions on how applicants should apply for an NCER grant is found on the NCER web site, http://www.epa.gov/ncer/rfa/forms/, Standard Instructions for Submitting a STAR Application. The necessary forms for submitting an application will be found on this web site.
The page limitations described in the Standard Instructions for Submitting a STAR Application in the NCER web site do not apply. The 15 page limit for the research narrative is extended to 35 pages, of which up to 25 pages may be used to describe the research approach - a detailed description for the first five-year phase and a less detailed description for the second five-year phase. The two-page limit for the quality assurance statement is extended to four pages. In addition, 1) four to five additional pages may be used to describe the administrative core and the responsibilities and support of the steering committee and 2) up to two additional pages may be used to describe a strategy to make data widely available, while protecting privacy or property rights, where applicable.
The need for a sorting code to be used in the application and for mailing is described in the Standard Instructions for Submitting a STAR Application. The sorting code for applications submitted in response to this solicitation is 2003-STAR-F1.
The deadline for receipt of the applications by NCER is no later than 4:00 p.m. ET, July 24, 2003.
Further information, if needed, may be obtained from the EPA officials indicated below. Email inquiries are preferred.
Barbara Glenn (202) 564-6913
Gail Robarge (202) 564-8301
Stacey Katz (202) 564-8201