9 December 2015
Tuberculosis infections are a significant cause of morbidity and mortality worldwide, and remain a major public health concern within the UK (which has one of the highest rates of TB infection in Europe). A major part of the UK public health strategy to reduce the number of TB infections centres around improved detection, diagnosis and outbreak management.
A plethora of retrospective research studies suggest whole genome sequencing (WGS) of M. tuberculosis (the main species of bacteria causing TB infections) presents an attractive alternative to current TB diagnostic methods that rely on a cumbersome process of sequential phenotypic and molecular tests. In theory, WGS can provide a diagnosis more quickly and could provide a full characterisation of drug susceptibility and relatedness to other infections (for outbreak investigation) from a single test. If this can be achieved in practice, it could mean getting the right patients the right drugs sooner, and could also improve population health more widely by guiding public health efforts to detect and resolve TB outbreaks.
Exciting results from the first prospective, multicentre trial of WGS for the diagnosis and antibiotic susceptibility testing of TB, were published last week in Lancet Respiratory Medicine. They show that the time taken to achieve a diagnosis i.e. to identify that a patient has TB and determine to which drugs their infection is susceptible, can be reduced by an average of three weeks. Furthermore they show that the laboratory-associated costs of achieving this more rapid diagnosis were slightly (7%) lower than the ‘old fashioned’ methods to which WGS was being compared.
While this trial is an important step forward, providing solid evidence of the technical and cost feasibility of WGS based TB diagnosis, there is some way to go before its benefits to patient and population health can be realised. What matters ultimately, when weighing up whether to invest in implementing any new diagnostic test, is the cost-effectiveness with which it can deliver improvements in health outcomes. At its simplest this might mean the new test produces equally effective results for lower cost compared to existing tests, or alternatively that it produces more effective results, by reducing turnaround time or increasing accuracy, for the same (or possibly higher) cost.
In the case of WGS for TB it is not yet clear how this cost-effectiveness equation will work out in practice. While this trial showed reduced costs to the microbiology laboratories of using WGS, it also showed that, for now, WGS is slightly less accurate than existing techniques. Without a full evaluation of the potential downstream clinical and public health benefits - which might include reduced delay in treatment, reduced healthcare intervention costs and hopefully reduced numbers of transmissions - it is difficult to know whether WGS for TB management really will be ‘worth it’.
As understanding of TB genomes increases it should be expected that the accuracy of genomic TB diagnosis will approach that of existing phenotypic tests, and that economies of scale, as more samples are processed routinely, might lead to reductions in sequencing cost per sample. Rolling out access to TB genomic testing nationwide, as has been done by Public Health England for Salmonella testing, might be justifiable purely on a ‘cost reduction’ but ‘health outcome neutral’ basis. However, the hopes of the multinational group involved in the study go beyond this modest goal and aim to significantly reduce the number of TB infections in their respective nations by reducing transmission. In this respect their epidemiological analysis of the sequenced TB genomes shows promising results, as they were able to link new cases to existing outbreaks, and in one example identify a new multidrug resistant cluster of cases.
These ‘genomic epidemiology’ studies offer tantalising visions of a future in which TB genomics enhances the accuracy and effectiveness of public health interventions by identifying, limiting or resolving outbreaks. However, genomic analysis will only ever be one small part of a long and complex pathway for the individual and population level management of TB. If the ‘rate limiting step’ in that pathway lies downstream of the genomic analysis e.g. if data management and sharing systems are ineffective, or there are not the resources to act upon the enhanced epidemiological information, then it will simply not be effective, whatever the cost.
As we set out in our pathogen genomics into practice report, genomics is an important part of the ‘solution’ for the future management of TB and potentially many other infectious diseases – but it is only a part. Our health systems and the societies in which they operate are complex and (in the UK at least) increasingly resource constrained. Such complexities must, as far as possible, be addressed in advance of implementation. Operationalising the technology itself is too often the ‘easy’ part. Changing the system to make the most effective use of it, to actually make people healthier, is where the really tough challenges lie.