Guide to the Application of Genotyping to Tuberculosis Prevention
Combining Genotyping and Epidemiologic
Data to Improve Our Understanding of
Clustering as a Surrogate Measure of Recent Transmission
TB programs that implement universal genotyping, either program-wide
or restricted to a county or adjacent group of counties, will have
a powerful tool to analyze the epidemiology of TB in their jurisdiction.
Programs that implement universal genotyping will be able to monitor
changes in the percentage of genotyping clustered cases. To the
extent that clustering reflects recent transmission, declines in
this percentage over time will reflect progress toward eliminating
There are several important caveats, however, in using genotype
clustering as a surrogate measure of recent transmission. Some of
these have already been described in the preceding discussion of
matching genotypes. These include insufficient discriminatory power
of genotyping methods, transmission of an endemic strain in a relatively
closed population, false-positive cultures, and laboratory error.
Each of these limitations leads to an overestimate of the rate of
One other factor also leads to an overestimate of recent transmission.
Two cases with matching genotypes are counted as two clustered cases,
but if one is the source case and the other is a secondary case,
they represent only one episode of recent transmission. Similarly,
three clustered cases, when one is the source case, represent only
two episodes of recent transmission. Some epidemiologists have suggested
that an adjustment should be made to account for this phenomenon
(Small 1994). They argue that the most accurate way to apply genotyping
results to make estimates of recent transmission is to exclude one
case from the count of each cluster.
Other factors may lead to underestimates of recent transmission.
For example, an isolate from the source case might not have been
genotyped, either because no culture was available or the isolate
was not sent for genotyping. This happens frequently at the start
of a new genotyping program, when there are few genotypes in the
database. It is common for the percentage of isolates that cluster
to increase over the first 2 or 3 years of a TB programís new genotyping
effort. Underestimation of recent transmission may also occur if
the source patient lived in a different jurisdiction from the secondary
patient; unless the two TB programs compared genotyping results,
the identical genotypes would not be recognized as matching. Emilia
Vynnycky and colleagues have developed sophisticated computer models
to accurately predict how these factors influence the accuracy of
clustering data (Vynnycky 2003)
Because of the shortcomings associated with using genotype clustering
as a surrogate measure of recent transmission, another alternative
should be considered. As discussed in more detail in Chapter 6,
Applying Genotyping Results to Tuberculosis Control Practices,
by combining genotyping results with epidemiologic information,
TB programs can obtain a more specific estimate of the amount of
recent TB transmission that is occurring in their jurisdictions.
We define epidemiologically confirmed recent transmission as a patient
who belongs to a genotyping cluster and shares known epidemiologic
links with another patient in that cluster. Monitoring the percentage
and the rate of recent transmission provides useful information
about the effectiveness of programs to interrupt transmission.
DTBE - Genotyping - Chap 4: Combining Geno and Epidemiologic
Data - Clustering as Surrogate Measure of Recent Transmission