Guide to the Application of Genotyping to Tuberculosis Prevention
Developing a Tuberculosis Genotyping Program
Clarifying Activities and Assigning Responsibilities
A TB genotyping program plan will involve many persons from many
organizations working together. It will be helpful if activities
and responsibilities are clarified at the beginning. Table 5.2 lists
some key activities and provides suggestions about which groups
may be responsible for each activity.
Table 5.2. Suggested activities and responsibilities
for TB genotyping programs.
|Establishing a TB Genotyping Program Plan
||Usually, this will be done by the state/large
city TB program. In unusual circumstances, and with prior approval
of the state TB program, a city that does not have a cooperative
agreement with CDC may submit a plan for approval.
|Deciding on initial scope of isolate submission:
a) only selected isolates; b) all isolates in state;
c) all isolates from predefined geographic area
|State/large city TB program
|Clarifying roles and assigning responsibilities
||State/large city TB program
|Submitting isolates to the genotyping laboratories
||Public health laboratories and/or clinical laboratories
will submit isolates. The state/large city TB program will provide
instructions on how this is to be done.
|Performing genotyping and reporting results to
the TB program
|Managing genotyping database and tracking isolates
that are submitted for genotyping
||State/large city TB program
|Receiving and recording genotyping laboratory
||State/large city TB program
|Responding to genotyping results
||State/large city and local TB programs
|Providing genotyping technical consultations
||Genotyping laboratory and CDC
|Providing epidemiologic consultations
||State/large city TB program and CDC
Deciding on Initial Scope of Genotyping Program: Three
Universal genotyping (i.e., submitting all isolates from a TB program
to the genotyping laboratories) holds great promise for improving
TB control. We believe that, within the next few years, programs
will want to have all their M. tuberculosis complex isolates
genotyped, just as they now have all their isolates analyzed for
drug susceptibility patterns. However, for programs to implement
a genotyping program, they will have to invest additional resources
to pay for shipping the isolates to the genotyping laboratories.
Programs may also have to hire additional staff or assign new duties
to existing staff so they are able to administer the program and
respond to newly identified genotyping clusters. Thus, initially,
some programs will not be able to implement universal genotyping.
There are three options for selecting the isolates that will be
submitted to the genotyping laboratories for genotyping.
Option 1: Universal submission of isolates program-wide
This option involves submitting one isolate from every patient
with a culture-positive specimen in a TB programís jurisdiction.
Advantages of universal genotyping. This option
provides the greatest benefit. Universal program-wide genotyping
provides the best understanding of the epidemiology of tuberculosis
transmission within the entire TB programís jurisdiction and
uncovers the greatest number of unexpected outbreaks, clusters,
and false-positive cultures.
Disadvantages of universal genotyping. This is
the most expensive option, and it requires a substantial commitment
Option 2: Universal submission of isolates from a selected
In this option, a specific geographic area is selected
(e.g., a particular county TB program or several adjacent county
programs), and all isolates that come from patients in the area
Advantages of universal genotyping in a subregion.
This option provides all the benefits of universal program-wide
genotyping as they apply to the specific region. It will be
more manageable than a program-wide effort. After a county universal
genotyping program is set up and running well, the program may
be expanded to other counties or to an entire state.
Disadvantages of universal genotyping in a subregion.
The full benefits of universal program-wide genotyping will
not be realized. If a TB program decides to adopt Option 3,
the following questions should be considered in selecting county
TB programs to participate:
- Is there buy-in from the county TB programs?
- Can isolate submissions be coordinated easily? (It will
be easier to work with a county where most isolates can be
submitted by one laboratory than with a county where isolates
would be submitted by multiple laboratories.)
- If more than one county will participate, are the counties
- Do the counties have a large number of TB cases? (Although
it may be easier to start in a county with a small number
of cases, the benefit will be greater in a county with many
- Does TB occur often in high-risk populations in the counties
Option 3: Selective submission of isolates
A policy of selective submission is a decision by the
TB program to submit only those M. tuberculosis isolates
that meet certain criteria. This option allows programs that cannot
implement universal genotyping to take advantage of the services
of the genotyping laboratory. For example, if the TB program suspects
that several TB cases are involved in the same chain of recent
transmission, isolates from these patients can be submitted to
the genotyping laboratory. Similarly, if a TB program or a laboratory
suspects that a diagnosis of TB is the result of a false-positive
culture, the isolate from the diagnosed case-patient and the isolate
that might have been identified as the possible source of the
false-positive culture can be submitted for genotyping.
Advantages of selective genotyping. It saves shipping
costs because only high-priority isolates are submitted. The
selective submission option will also minimize the number of
times a TB program will need to conduct a cluster investigation,
because the TB program will submit for genotyping only those
isolates from high-priority suspected clusters.
Disadvantages of selective genotyping. First,
selective genotyping does not allow a TB program to realize
the full benefit of genotyping. Because only selected isolates
are genotyped, the TB program will be less likely to learn about
unsuspected recent transmission. With selective genotyping,
you can confirm only what you already suspect. For similar reasons,
the discovery of unsuspected false-positive cultures, which
is one of the most important benefits of universal genotyping,
is not possible with selective genotyping.
The second disadvantage of selective genotyping is that it
requires several steps to locate and request submission of isolates;
these steps are not necessary with universal genotyping. For
example, under a policy of selective submission, if an outbreak
is suspected and a TB program wants to submit isolates from
the patients who are considered part of the outbreak, the TB
program must determine which patients have culture-positive
isolates and what laboratories have those isolates. The TB program
must send a request to the laboratories; the laboratories must
locate and possibly subculture the isolates before they can
be sent to the genotyping laboratories. With universal genotyping,
all isolates are submitted automatically for genotyping; no
person at the TB program would need to identify isolates for
genotyping or to make an individual request to the laboratories,
and the laboratories might have prepared an isolate for shipment
as a routine part of their procedures for processing cultures.
Summing Up: Deciding
on Initial Scope of Genotyping Program
One of the first decisions a TB program must make is the
initial scope of their genotyping program. There are three
Universal genotyping program-wide provides the most
benefit, but it requires a substantial investment in program
Universal genotyping for a subregion (a single county
or adjacent county TB programs) provides some of the benefits
of statewide universal genotyping but is easier to initiate
and costs less.
Selective genotyping is the easiest to initiate and
the least expensive.
Identifying Laboratories that Will Submit Isolates to the
The TB program that opts for universal genotyping, either program-wide
or within a particular county, needs to identify the laboratories
in their jurisdiction that will submit M. tuberculosis isolates
to their genotyping laboratory. The TB program that opts for selective
genotyping may wait to contact submitting laboratories until the
program identifies specific isolates to be submitted.
If all M. tuberculosis isolates are sent to the state public
health laboratory for routine isolation and identification or for
drug susceptibility testing, it will be easier to have that laboratory
be responsible for submitting isolates to the genotyping laboratory.
If the state public health laboratory does not receive all isolates,
the TB program should explore the feasibility of establishing a
new state health regulation that calls for all M. tuberculosis
isolates to be submitted to the state laboratory. The regulatory
language used by the New York City TB program to have all isolates
submitted to their public health laboratory is available for review
on the WebBoard at http://web-tb.forum.cdc.gov.
If a new regulation is not feasible or is delayed, and the state
public health laboratory cannot be the only entity that will submit
isolates to the genotyping laboratory, a process will have to be
implemented to identify the laboratories that isolate and identify
M. tuberculosis from patients in the state or county. This
will include state and county public health laboratories, private
laboratories, large commercial laboratories (which may include out-of-state
laboratories), and laboratories at medical centers and hospitals.
Laboratories perform various types of services. For the purpose
of submitting isolates, only laboratories that identify isolates
as M. tuberculosis complex should be considered. Laboratories
that isolate mycobacteria but do not process them further do not
have to be considered, although such laboratories may be conduits
for reporting results to clinicians or to the TB program.
Many laboratories isolate and identify M. tuberculosis and
then send the isolates to a state or reference laboratory for susceptibility
testing. In these cases, either the originating or reference laboratory
could be designated as the entity to submit isolates for genotyping.
Asking the originating laboratory to submit isolates will provide
the most rapid turnaround, but this will require the originating
laboratory to ship the isolate twice: once to the reference laboratory
and once to the genotyping laboratory. Many laboratories may find
The Division of Laboratory Systems at CDC developed the National
Laboratory Database (NLD) of all Clinical Laboratory Improvement
Amendments (CLIA)-approved laboratories in the United States. CDC
provides access to this database to all 50 state public health laboratory
directors. One of the variables is mycobacteriology, which
allows a state public health laboratory director to download a list
of every laboratory that performs some level of mycobacteriology
testing. The system also allows the state laboratory director to
download an accurate mailing list of these laboratories. TB programs
that want to use the NLD should request approval from their state
laboratory director, asking that the director grant NLD access to
a specific person by sending an email to Dr. Rex Astles at JAstles@cdc.gov.
Establishing a Communications Plan
Effective communication among the state and local TB programs,
state laboratory, submitting laboratories, and the genotyping laboratory
is critical to the success of genotyping. Planning for an effective
communications system should be one of the initial steps in developing
a genotyping program. The system (e.g., a shared web-based database,
e-mail, telephone, or fax) will depend on local capabilities. Approaches
to ensure that patient confidentiality is maintained should be addressed.