1. Introduction {#s0005}
===============

Despite major advances in vaccines, diagnostics, therapeutics and infection control measures, the "unfinished agenda" of infectious diseases remains a global threat. The Global Burden of Disease (GBD) Study 2013 reports that lower respiratory tract infections, diarrhoeal disease, HIV, and malaria were four of the top ten causes of disease burden globally, as measured by disability-adjusted life years (DALYs) ([@bb0155]). These four disease areas, plus tuberculosis (TB), comprised five of the top eleven causes of death worldwide in 2013 ([@bb0065]). Infectious diseases generate a large economic burden ([@bb0060]) with antimicrobial resistance (AMR), the subject of a World Health Organization (WHO) action plan ([@bb0180]) and a priority for the United Kingdom (UK) ([@bb0005]), [@bb0030], and the US Centers for Disease Control and Prevention (CDC) ([@bb0010]), projected to cost an estimated \$100 trillion by the year 2050 if unadressed ([@bb0015]).

Research is essential to improve the evidence base for policy and clinical practice. The UK research funding landscape has several national and international awarding bodies that invest in pre-clinical (laboratory) science, observational studies, clinical trials, and translational research, with significant commitments to infectious disease research. Earlier research by the Research Investments in Global Health study (ResIn, [www.researchinvestments.org](http://www.researchinvestments.org){#ir0005}) has systematically analysed public and philanthropic awards totalling £2.6 billion to UK institutions for infectious disease from 1997 to 2010, for funding awarded by infectious disease, microbiology and type of science ([@bb0120]), including for respiratory infectious disease research ([@bb0085]) and pneumonia ([@bb0105]), sepsis ([@bb0040]), AMR ([@bb0090]), and sexually-transmitted infections ([@bb0110]). Tracking research and development (R&D) investments provides information and evidence to inform policy on funding decisions. We present an update to the systematic analysis of infectious disease research awarded by public and philanthropic funders to UK institutions from 2011 to 2013, and assess funding from 1997--2013 against global measures of mortality, DALYs and years lived with disability (YLD) across three time points.

2. Methods {#s0010}
==========

Our methods for the 1997--2010 analysis are described in detail elsewhere ([@bb0085], [@bb0090], [@bb0115], [@bb0095], [@bb0075], [@bb0080], [@bb0105], [@bb0110], [@bb0100], [@bb0055], [@bb0050]) and adapted in subsequent peer-reviewed publications ([www.researchinvestments.org/publications](http://www.researchinvestments.org/publications){#ir0010}).

The methods for the updated analysis are broadly similar, in that we systematically examined award data from 585 public and philanthropic funding bodies by either searching the databases and information on their publically available websites, requesting data directly or searching other funding databases. From the information gathered, we manually screened each study individually for relevance to infectious disease research. We excluded studies not immediately relevant to infectious disease, symposium grants, studies related to purely veterinary or plant infectious disease (but included animal health research incorporating a clear zoonotic component), research where a viral vector was used in relation to non-communicable disease, and awards that were led by a non-UK institution, but had UK collaborators. Of the studies included in the final dataset, all had a title or brief descriptor and 65.1% had either an abstract attached or further information sourced from the internet (e.g. institutional webpages, clinical trials databases). Private sector data were not available to analyse in the same detail and therefore excluded.

Where awards were received from an international funder, currencies were converted to UK pounds using the mean exchange rate in the year of the award. All grant funding amounts were adjusted for inflation and reported in 2013 UK pounds. Awards from 1997--2010 had been previously adjusted for inflation to 2010 levels, but have here also been adjusted and reported in 2013 UK pounds to allow for updated comparison between years. Ongoing data management and revision to the overall dataset has resulted in 5 less studies (0.001% change) than previously reported. Unfunded studies were excluded.

Each study in the dataset was reviewed by MGH and assigned to as many disease categories as appropriate. Authors VN and NK provided support for this categorisation process. Studies were also allocated to one of five categories along the R&D pipeline: pre-clinical; phase I, II, or III; product development; public health; and cross-disciplinary research. The introduction of the cross-disciplinary category was a refinement of the previous methodology prompted by an increasing number of these types of awards (defined as an award containing significant components of a study that covers two areas along the R&D pipeline). We did not retrospectively apply this new category to the 1997--2010 dataset owing to resource constraints. The public health research category was previously entitled 'implementation and operational research'. The change in name better reflects the content of this category, and has not involved any change in which studies are categorised here.

Provisional datasets were circulated to all authors for review and comment. Further checks involved authors JRF, VN and NK cross-checking 20% sections of randomly-selected rows of data with any disagreements settled by consensus, and also providing an opinion on any studies where initial categorisation proved difficult. Authors MGH and JRF further considered difficulties in categorisation between phase I--III studies, and the product development category that includes phase IV research. Final datasets were then again circulated for further review by all authors. Two fixed marginal κ scores were calculated and showed 0.95 for level of agreement on the 'type of science' categorisation, and 0.91 for application of the disease categories, highlighting high levels of independent agreement in the categorisation process.

As per the earlier analysis ([@bb0120]), the category of antimicrobial resistance includes antibacterial, antiviral, and antifungal resistance. Reference to diagnostics includes screening programmes. Reference to sexually transmitted infections excludes HIV which is defined in its own category, and neglected tropical diseases were categorised based on the infections focused on by WHO (<http://www.who.int/neglected_diseases/diseases/en/>). Awards were defined as global health if they i) were considered to pursue a clear non-UK focus (e.g. 'tuberculosis in Kenya'), or ii) focused on diseases not endemic in the UK (e.g. malaria).

Available on the ResIn website (<http://researchinvestments.org/about-the-study/study-methodology/>) is the list of included funders (and excluded funders with reason for exclusions), list of keywords used to search funder\'s website, and examples of (and comment on) the definitions and categorisations. Stata (V13) software was used for data analysis.

Global mortality and DALY data were available at time points 2004, 2010 and 2013. Time points for global YLDs were 2005, 2010 and 2013. All burden data were sourced from the findings of the Global Burden of Disease study, for 2013 ([@bb0155], [@bb0065], [@bb0020]) and for 2010 ([@bb0020], [@bb0160], [@bb0145]). Burden data from 2004/05 were obtained directly from colleagues at the Institute for Health Metrics and Evaluation, Washington. As defined by the GBD study, YLDs per person from a sequela are equal to the prevalence of the sequela multiplied by the disability weight for the health state associated with that sequela. YLDs for a disease or injury are the sum of the YLDs for each sequela associated with the disease or injury ([@bb0170]). DALYS are the product of adding YLLs and YLDs for each age--sex--country group ([@bb0155]).

In order to allow direct comparison of relative investment with global health metrics across disease areas and between different time periods, metrics were developed to show 'investment per mortality/DALY/YLD observed', and these were created using the following equation --- (cumulative research investment up to the year before the time point / number of deaths, DALYs or YLD at time point) / number of years of investment included.

For example, for assessment of HIV mortality at the 2004 time point, we took the sum of HIV research investment 1997--2003 (£238,900,938) and divided that by number of deaths reported in 2004 (2,040,000), and divided the result by 7 (the number of years of investment included) to get an 'investment per mortality observed' metric of £16.73.

The use of cumulative investment and the division by number of years included aimed to reduce the impact of the volatility of annual research funding and short periods between time points.

Ranking scores of the investment metrics were developed for each infection and across each time point. Infections were ranked in order of relative investment against burden from high to low and assigned a score (from 1 to 25). The mean ranking scores across time points and across mortality, DALY and YLD were used to illustrate relative levels of investment.

In 2004 mortality, 2005 YLD and all 2013 datasets, only aggregated data was available for diarrhoea and enteric infectious disease and lower respiratory tract infections. For *Salmonella*, *Escherichia coli*, *Shigellosis*, *Vibrio cholerae*, *Campylobacter*, influenza and pneumonia, proportional estimates were compiled using disaggregated data from the 2010 dataset.

3. Results {#s0015}
==========

The analysis for 1997--2013 analysis included funding of £3.7 billion across 7398 awards ([Table 1](#t0005){ref-type="table"}). Mean funding for all infectious diseases was £219.1 million per year (435 awards annually). Mean funding per award was £503,524 (SD £1,412,776) with median funding per award of £192,143 (IQR £63,189--418,015).

Across 2011--2013, there were additional 1232 awards with total new funding of £917.0 million. Mean annual funding was greater in 2011--2013, amounting to £305.7 million across 411 awards each year. Mean funding per award was £744,286 (SD £1,360,777), with median funding per award at £315,918 (IQR £156,283--779,794).

[Table 1](#t0005){ref-type="table"} shows comparisons of funding for specific infection and disease area in 1997--2013 and specifically the addition of 2011--2013 data. Total and proportional funding for antimicrobial resistance (5.8% of all infection research), healthcare-associated infections (4.71%), and viral hepatology (5.1%) increased in 2011--13 compared with 1997--2010. Relative funding for sepsis (0.24% of all infection research), sexually-transmitted (1.86%) and neurological infections (0.46%) declined in 2011--2013 compared with 1997--2010. An observed 36.2% of the total investment was directly related to global health. There was no public or philanthropic research investment for Ebola or other haemorrhagic fevers in 2011--2013. There were large increases in funding for new products, specifically diagnostics, therapeutics and vaccines.

There is volatility in annual research funding though an overall increase between 1997 and 2013 ([Fig. 1](#f0005){ref-type="fig"}a). The Wellcome Trust is the largest investor in research, having funded 2285 studies (30.9%) totalling £935.0 million (25.1%), followed by the Medical Research Council (£924.9 million, 24.8%). The European Commission funded 12.9% of total investment across 1997--2013, and this increased to 21.6% specifically across 2011--2013, ahead of the Wellcome Trust (20.9%) and slightly behind the MRC (21.9%) (Supplementary 1). Alongside these three funders, the National Institute for Health Research (NIHR, main funding stream of the UK Department of Health), Biotechnology and Biological Sciences Research Council (BBSRC) and the Bill & Melinda Gates Foundation combined contributed 84.1% of the overall investment. The remainder was provided by institutions such as the US National Institutes for Health (NIH), UK government departments, UK research councils, other research charities and professional bodies and societies.

The proportion of funding awarded by the type of science (supplementary 2, [Fig. 1](#f0005){ref-type="fig"}b) show a gradual increase in investment for public health research with slight decline for pre-clinical science. Pre-clinical science overall receives the greatest investment of £2.2 billion (59.4%), followed by public health research (£954.6 million; 25.9%), with relatively little public or philanthropic investment for phase I--III trials (£207.3 million; 5.6%) or product development studies (£234.7 million, 6.3%). Cross-disciplinary research accounted for a small number of awards (0.7% overall, 4.0% in 2011--2013), but a greater proportion of the funding (£105.4 million; 2.8% overall, 11.5% in 2011--2013) and these studies were often consortia-led or programme grants.

Across three time points (2005, 2010, 2013), YLDs for infectious diseases broadly declined ([Table 2](#t0010){ref-type="table"}, [Fig. 2](#f0010){ref-type="fig"}). The median 'investment by YLD observed' metric was highest in 2013 (£6.01 compared with £3.56 overall). Acute hepatitis C and trypanosomiasis consistently received the greatest relative investment respectively ([Table 2](#t0010){ref-type="table"}). Investment by YLD observed for influenza greatly increased in 2013 (£68.69, compared with £10.93 in 2010, after the 2009 pandemic). Infections such as shigellosis, cholera, syphilis and gonorrhoea were typically amongst those receiving the lowest relative investment (less than £1.00 per YLD observed).

The relative level of investment per death, DALY or YLD for all infections combined consistently increased over time ([Table 2](#t0010){ref-type="table"}, [Table 3](#t0015){ref-type="table"}, [Table 4](#t0020){ref-type="table"}). When considering time points 2004, 2010 and 2013, the median investment by mortality observed was £17.20, but greatest in 2013 (£31.16). HIV and malaria investments were above the median level at each time point; tuberculosis was below the median level ([Table 3](#t0015){ref-type="table"}, [Fig. 3](#f0015){ref-type="fig"}). Compared to mortality, little investment was directed towards cholera, syphilis and pneumonia. Vaccine-preventable diseases such as diphtheria, measles and pertussis were mostly ranked as poorly-invested, though their respective investment by mortality observed noticeably increased in 2013 as global burdens declined. The 'investment per DALY observed' metric ([Table 4](#t0020){ref-type="table"}, [Fig. 4](#f0020){ref-type="fig"}) demonstrated similar findings to the mortality metric, with pneumonia appearing poorly-invested compared to other particularly high-burden infections such as malaria, and cholera, syphilis and pertussis also receiving little funding. Acute hepatitis C, African trypanosomiasis and chlamydia demonstrated the highest relative investment when compared to DALYs.

Ranking infections by investment and disease burden in 2013, [Table 5](#t0025){ref-type="table"} describes how HIV (9th) and malaria (10th) were mid-ranking diseases, with tuberculosis (14th) and pneumonia (20th) ranked lower. Acute hepatitis C, African trypanosomiasis and leishmaniasis were the top three infections, and pertussis, cholera and syphilis the bottom three. Diphtheria was ranked in the lowest three when compared against mortality and DALYs, whilst gonorrhoea was ranked in the lowest three when compared against YLD.

4. Discussion {#s0020}
=============

We identified 7398 awards for infectious disease research awarded to UK institutions across the 17 year time period of 1997--2013, with total funding of £3.7 billion. Relative to measures of investment compared to global mortality, DALYs and YLD, acute hepatitis C, trypanosomiasis and leishmaniasis rank highly whilst *Shigellosis*, pertussis, cholera and syphilis consistently rank lowest; tuberculosis typically ranked lower than HIV or malaria, and pneumonia appears to receive particularly low levels of investment compared to mortality and DALYs. The overall level of investment and the median investment by mortality, DALY and YLD observed increased in 2013 compared with previous time points, owing to both increases in research investment and decreases in the global burden of infectious disease.

The comparison with global burden of disease and the development of associated metrics demonstrates the need for consideration of more than one measure of burden. Pneumonia, a disease with relatively high mortality, receives low levels of research investment when considering just mortality or DALYs, but ranks higher when considering lifelong measures of burden such as YLDs. Chlamydia, a disease of low mortality, ranks highly when comparing investment with mortality but the YLD ranking is lower. Chronic infections are also difficult to account for, as demonstrated by the high ranking of acute hepatitis C, which does not fully take into account the chronic and undiagnosed burden or the projected future burden.

Several of the infections studied are vaccine-preventable, such as measles, pertussis and diphtheria, and policymakers need to decide whether to fund, for example, operational research to identify improvements in the delivery process of vaccine, or to invest more heavily in implementation measures known to be effective. Expanding on this work to incorporate further measures of burden across different time points and to take into account proportions of funding for each type of science would strengthen these models. Replication of the study using data from other countries and in non-communicable disease area would also provide a more complete picture of diseases where there have been adequate or inadequate investment. Further work to decipher the impact of predominantly UK-focused funders, such as the NIHR, and the global funding remit of the organisations such as the Wellcome Trust would also be useful.

There are other published analyses that have similar aims in terms of considering investment and burden. Consideration of NIH funding in 2006 suggested a modest correlation with USA disease burden from 2004, ([@bb0070]) with comparable findings in analyses from Australia ([@bb1000]) and Norway ([@bb0140]), showing variable correlation depending upon the chosen burden metric and whether that metric considered national or global burden. Thus, policymakers have a decision to make about the extent to which there is targeting of investment on health burdens within their own country, and how much funding targets international priorities. These decisions will be driven to an extent by the remits of existing funding agencies, plus also the existing research expertise in the UK. Disease areas such as the NTDs appear well-funded here, relative to their global disease burden, and this is may be in part due to previous and ongoing excellent performance by individuals and institutions in addressing these areas. In terms of the location of research investment activity, the UK demonstrably provides greater relative international investment in nations where there are colonial ties ([@bb0045]). It may be that other nations also favour countries in which they have historic connections (and there are good reasons for doing so, such as a common language or infrastructure requirements); however, this may also mean that some countries are neglected in terms of receiving research investment from which they could greatly benefit.

Funding for infections with pandemic potential remains inconsistent and it is difficult to project accurate future burdens of new and emerging infectious diseases. The UK influenza research portfolio is now arguably relatively strong, combined with a Department of Health focus to identify research gaps and priorities in this area ([@bb0135]). The emergence of the large Ebola outbreak in West Africa over 2014 and 2015 has highlighted how little research there has been by UK institutions prior to 2014 on filoviruses; an unpublished analysis using ResIn data demonstrates that the US NIH is the only funder with a track record of sustained funding in this area. Reactive efforts across 2014 and beyond will greatly increase that total research investment; however, the examples of Ebola and novel coronaviruses with pandemic potential ([@bb0085]) show that there is a need for a proactive approach in terms of commissioning, capacity-strengthening and carrying out research in diseases that have potential to impact on global health security (though this area of commissioning faces significant challenges). Decisions around resource allocation for disease eradication may reflect the interests of specific donors and high-profile individuals, such as former US President Jimmy Carter and his efforts towards eradicating dracunculiasis (Guinea worm) ([@bb0130]), though most investment here would be considered implementation rather than research. In 2015, the UK government announced a high-profile implementation and research investment in collaboration with the Bill & Melinda Gates Foundation to advance knowledge against infectious diseases, particularly malaria ([@bb0125]). Clearly, there are other factors beyond current and projected disease burdens that should influence decisions around research investment priorities, such as the effectiveness of available interventions, what constitutes the 'best buy' for a particular health service and consideration of health inequity in neglected populations ([@bb0175]). There should also be reflections on what research is feasible and the likelihood of advances in knowledge if investment is targeted in specific disease or geographical areas. A checklist for health research priority setting, with the aim of achieving maximum public health benefit, has been suggested previously ([@bb0165]), and the data presented here showing the relative scale of investment compared to disease burden can usefully inform the commissioning process for research that assesses how to alleviate the impact of disease on public health.

There have been demonstrable shifts in the proportions of the type of science allocated to some disease areas, and this will affect the likely temporal impacts of R&D on public health and patient care and thus the burden of disease. For example, over 80% of gastroenterology research was pre-clinical in 1997--2010; across 2011--2013, less than half was pre-clinical with relatively equal sums of money for the other four phases of research. This may be the result of the previous pre-clinical research being translated into tools, products or knowledge in other areas of the research pipeline, and may have contributed to the reduction in global burden of disease observed in enteric infections in 2013. The level of investment by the private sector in new tools such as vaccines, therapeutics and diagnostics for infectious diseases is important but uncertain given the low market attractiveness for these conditions which predominantly affect lower income and middle income countries, though it is plausible that investment decisions in the public, philanthropic and private sector are made as a result of some level of interaction between the sectors. There are examples of public--private product development partnerships for infections such as malaria and TB, while that for maternal and child health, where there is also low market attractiveness, has been lacking ([@bb0035]). Although there has been progress made with transparency of reporting in the pharmaceutical and biotechnology industries ([@bb0025]), commercial sensitivities mean that it is difficult to obtain investment data to analyse in similar detail to the awards included here.

The low levels of research investment for syphilis and gonorrhoea remain ([@bb0120], [@bb0110]), both in terms of total funding but also when compared to disease burden. Given the increasing levels of antibiotic resistance in strains of *Neisseria gonorrhoeae*, and the continuing high burden of both these otherwise-treatable infections, they seem an area worthy of greater focus by UK research institutions and funders. Sepsis remains hugely problematic in many healthcare settings, and the research portfolio needs to be increased to reflect this.

The temporal trends in funding for infectious disease research has been noted as being volatile ([@bb0050]), for example the peak in year 2000 ([Fig. 1](#f0005){ref-type="fig"}a) being partly due to markedly increased contributions from the Bill & Melinda Gates Foundation in that year (£40.1 million, compared with zero UK research investment in 1999 or 2001). This will result in fluctuations in levels of funding for several infections; for example here across 1997--2010 and 2011--2013, investments for Candida proportionately increased and investments for HPV decreased The rationale for fluctuations in funding are complex, and will reflect various issues such as funder priorities, numbers of applications received by those funders, disbursement of research funds over the study period, research capacity in each topic area, and potentially the quality of burden data available.

This study has several limitations, some of which have been described previously ([@bb0120]). An additional limitation is that our analyses will exclude much infrastructure funding that some funders invest in quite heavily and this may underestimate total investment in infectious disease research as well as the contribution of specific funders. As described above, the lack of private sector investment information leaves a data gap. Analyses have not taken into account proportions of awards allocated to indirect or estate costs. Any distribution of funding from the lead centre to collaborating partners is also not documented. Categorisation is subjective, but checks by at least one other author reduce the impact of any observer error. This analysis is also vulnerable to the effects of any changes in methodology of the GBD study, and there will also be uncertainty in the disease estimates calculated in the GBD analyses.

Public and philanthropic research funding for infectious diseases has increased in the time period 2011--2013 as compared with previous years, with greater mean and median award amounts, indicating a shift towards funding award types such as consortia or programme grants. Measuring these investments against the global burden of disease highlight areas such as influenza and trypanosomiasis where the UK has relatively strong investment and probable research strengths, but areas such as sepsis, pneumonia, syphilis and gonorrhoea remain areas of relative underinvestment, and should be considered by funding organisations and policymakers. Co-ordinated efforts across the global health community must consider research investment in emerging infectious diseases and pathogens of pandemic potential. By demonstrating potential inequities in allocation of investment and disease burden, analyses by the ResIn study can contribute to priority setting by funders and inform strategy of policymakers, government departments and research institutions.

Funding {#s0025}
=======

There was no funding source for this study.

Ethical approval {#s0030}
================

An ethics statement was not required for this work.

Contributors {#s0035}
============

MGH and JRF designed the study. MGH wrote the submission with edits by all authors. MGH, JRF, NK and VN collected and categorised the data. AH and RA provided commentary on the dataset and interpretation of the results. All authors gave comments on draft and final versions of this manuscript.

Competing interests {#s0040}
===================

The authors have no conflicts of interest to declare.

Appendix A. Supplementary data {#s0045}
==============================

Supplementary materials 1Supplementary materials 2

The authors would like to acknowledge the input of the Infectious Disease Research Network ([www.idrn.org](http://www.idrn.org){#ir0025}) and the funding agencies who contributed data to these analyses.

Supplementary data to this article can be found online at [http://dx.doi.org/10.1016/j.ebiom.2015.12.016](10.1016/j.ebiom.2015.12.016){#ir0030}.

![a) Aggregate and b) proportionate funding from 1997--2013 by type of science along the research and development pipeline (1997--10 data published previously ([@bb0120])).](gr1){#f0005}

![Investment by years lived with disability (YLD) observed for selected infections and across three time points.](gr2){#f0010}

![Investment by mortality observed for selected infections and across three time points.](gr3){#f0015}

![Investment by DALYs observed for selected infections and across three time points.](gr4){#f0020}

###### 

Total funding, number of studies and mean and median award size of research investment by infection 1997--2013. SD, standard deviation. IQR, inter-quartile range.

                                      Investment 1997--2013   Investment 2011--2013                                                                                                 
  ----------------------------------- ----------------------- ----------------------- ------- ------------------------ ------------------------------ ------ -------- ------------- --------
  Overall                             7398                    3,725,073,507           n/a     503,524 (1,412,776)      192,143 (63,189--418,015)      1232   n/a      916,960,747   n/a
  Disease areas and products                                                                                                                                                        
   Antimicrobial resistance           413                     164,419,467             4.4%    398,110 (901,417)        155,794 (44,065--347,091)      76     6.17%    53,195,899    5.80%
   Global health                      1712                    1,348,277,988           36.2%   787,545 (2,468,415)      253,262 (77,735--589,359)      306    24.84%   343,532,187   37.46%
   Gastroenterology                   903                     355,186,553             9.5%    393,340 (687,605)        218,799 (82,364--394,549)      114    9.25%    90,313,344    9.85%
   Healthcare-associated infections   348                     105,957,588             2.8%    304,475 (750,448)        71,490 (10,656--252,931)       51     4.14%    43,165,873    4.71%
   Hepatology                         366                     125,058,113             3.4%    341,688 (794,679)        128,340 (43,420--290,954)      44     3.57%    46,794,839    5.10%
   HIV                                919                     651,351,095             17.5%   708,760 (2,350,940)      181,628 (41,468--481,721)      155    12.58%   135,569,246   14.78%
   Neglected tropical diseases        490                     323,791,367             8.7%    660,798 (2,191,508)      276,730 (107,065--527,303)     83     6.74%    75,444,667    8.23%
   Neurology                          399                     151,371,666             4.1%    379,377 (939,438)        169,212 (70,749--390,007)      60     4.87%    4,226,646     0.46%
   Respiratory                        1230                    556,045,105             14.9%   452,069 (838,744)        207,736 (67,471--445,418)      219    17.78%   145,182,110   15.83%
   Sepsis                             86                      24,762,825              0.7%    287,939 (577,197)        151,855 (54,291--272,451)      7      0.57%    2,210,944     0.24%
   Sexually transmitted infections    402                     166,144,022             4.5%    413,293 (1,035,635)      112,263 (19,251--269,686)      24     1.95%    17,014,003    1.86%
  Diagnostics                         484                     202,271,238             5.4%    417,915 (1,055,385)      106,001 (19,758--296,732)      77     6.25%    93,692,388    10.22%
   Therapeutics                       788                     662,160,655             17.8%   840,305 (2,683,243)      231,142 (62,947--639,642)      262    21.27%   217,159,123   23.68%
   Vaccinology                        490                     374,959,878             10.1%   765,224 (1,556,168)      266,315 (104,809--730,657)     122    9.90%    119,905,881   13.08%
  Specific infection or disease                                                                                                                                                     
   African Trypanosomiasis            170                     98,621,900              2.6%    580,128 (1,070,225)      288,393 (156,960--505,168)     35     2.84%    29,561,488    3.22%
   *Aspergillus*                      32                      9,381,561               0.3%    293,173 (680,033)        68,304 (23,920--231,642)       6      0.49%    4,254,846     3.14%
   *Campylobacter*                    113                     35,796,296              1.0%    316,781 (497,139)        240,419 (95,468--346,045)      26     2.11%    9,775,861     1.07%
   *Candida*                          87                      31,410,745              0.8%    361,043 (461,554)        282,390 (92,281--416,521)      11     0.89%    6,676,377     0.73%
   Chagas disease                     18                      5,284,555               0.1%    293,586 (222,290)        233,625 (175,747--372,486)     0      0.00%    0             0.00%
   Chlamydia                          119                     25,899,326              0.7%    217,641 (593,623)        60,833 (12,590--196,419)       7      0.57%    2,783,510     0.30%
   Cholera                            7                       1,154,507               0.0%    164,929 (123,277)        89,667 (51,193--287,951)       0      0.00%    0             0.00%
   Clostridium                        97                      56,061,419              1.5%    577,952 (1,089,221)      226,732 (49,926--475,684)      19     1.54%    17,009,293    1.85%
   Cytomegalovirus                    79                      35,695,572              1.0%    451,842 (673,587)        220,703 (118,302--531,000)     11     0.89%    5,287,629     0.58%
   Dengue                             38                      54,430,748              1.5%    1,432,388 (5,674,662)    309,695 (124,361--693,323)     9      0.73%    6,236,268     0.68%
   Diphtheria                         2                       149,094                 0.0%    n/a                      n/a                            0      0.00%    0             0.00%
   Ebola                                                                              0.0%                                                            0      0.00%    0             0.00%
   *Escherichia coli*                 130                     38,984,636              1.0%    299,881 (290,578)        234,560 (119,663--380,995)     23     1.87%    10,782,819    1.18%
   Epstein-Barr Virus                 155                     51,901,868              1.4%    334,850 (479,035)        164,142 (52,255--389,593)      9      0.73%    4,333,912     0.47%
   Gonorrhoea                         20                      1,448,016               0.0%    72,400 (99,604)          14,485 (3963--146,098)         2      0.16%    440,305       0.05%
   Helicobacter                       104                     18,233,832              0.5%    175,325 (280,233)        95,172 (12,217--203,294)       3      0.24%    2,282,283     0.25%
   Helminths                          158                     80,232,248              2.2%    507,799 (1,221,547)      251,698 (93,055--459,074)      8      0.65%    6,852,922     0.75%
   Hepatitis B                        82                      26,834,637              0.7%    327,251 (708,712)        87,810 (24,062--238,425)       13     1.06%    10,996,796    1.20%
   Hepatitis C                        272                     110,257,438             3.0%    405,358 (926,977)        141,135 (50,250--301,331)      36     2.92%    43,153,957    4.71%
   HIV                                919                     651,351,095             17.5%   708,760 (2,350,940)      181,628 (41,468--481,721)      155    12.58%   135,569,246   14.78%
   Human papillomavirus               164                     62,219,508              1.7%    379,387 (872,744)        119,037 (39,642--260,832)      17     1.38%    5,994,339     0.65%
   Herpes simplex virus               55                      26,750,879              0.7%    486,379 (733,513)        225,701 (60,655--458,073)      7      0.57%    3,163,889     0.35%
   Influenza                          194                     126,643,152             3.4%    652,799 (1,124,119)      308,455 (164,025--736,503)     53     4.30%    39,139,703    4.27%
   Leishmaniasis                      89                      52,894,292              1.4%    594,317 (868,448)        309,522 (121,761--582,645)     11     0.89%    7,257,334     0.79%
   Leprosy                            2                       633,855                 0.0%    n/a                      n/a                            0      0.00%    0             0.00%
   Listeria                           13                      6,566,639               0.2%    505,126 (452,060)        263,445 (139,604--730,472)     0      0.00%    0             0.00%
   Lymphatic filariasis               10                      57,693,197              1.5%    5,769,320 (11,200,387)   806,101 (208,913--3,247,287)   3      0.24%    5,986,094     0.65%
   Malaria                            621                     518,734,860             13.9%   835,321 (2,413,049)      256,064 (75,813--641,805)      117    9.50%    137,212,998   14.96%
   Measles                            13                      6,556,866               0.2%    504,374 (463,858)        331,040 (77,576--777,779)      1      0.08%    1,113,633     0.12%
   Meningitis                         264                     90,609,407              2.4%    343,217 (1,060,577)      155,610 (73,893--266,103)      42     3.41%    32,968,225    3.60%
   Norovirus                          23                      13,181,682              0.4%    573,116 (937,560)        218,767 (61,583--533,797)      11     0.89%    7,580,760     0.83%
   Onchocerciasis                     8                       7,755,554               0.2%    969,444 (1,315,292)      217,587 (30,798--2,005,428)    3      0.24%    5,986,094     0.65%
   Pertussis                          13                      4,108,262               0.1%    316,020 (250,671)        341,788 (46,284--539,766)      4      0.32%    1,527,779     0.17%
   Pneumonia                          137                     59,051,642              1.6%    431,033 (820,052)        206,399 (61,652--401,771)      35     2.84%    28,849,125    3.15%
   Polio                              13                      6,786,968               0.2%    522,074 (596,514)        419,773 (67,163--580,209)      9      0.73%    5,978,072     0.65%
   *Pseudomonas*                      59                      11,577,984              0.3%    196,237 (239,174)        153,990 (29,367--263,384)      16     1.30%    4,553,921     0.50%
   Rotavirus                          22                      7,752,326               0.2%    352,378 (423,329)        179,221 (148,949--352,758)     3      0.24%    1,097,942     0.12%
   Respiratory syncytial virus        56                      20,984,547              0.6%    374,724 (482,391)        197,172 (51,855--527,461)      11     0.89%    2,756,796     0.30%
   *Salmonella*                       168                     81,422,224              2.2%    484,656 (595,724)        291,574 (172,554--518,393)     23     1.87%    21,291,316    2.32%
   Schistosomiasis                    50                      45,767,421              1.2%    915,348 (3,963,046)      215,294 (65,146--469,526)      3      0.24%    2,069,845     0.23%
   Shigellosis                        12                      7,390,226               0.2%    615,852 (534,875)        527,553 (148,386--923,817)     3      0.24%    3,815,542     0.42%
   Syphilis                           5                       1,112,066               0.0%    222,413 (152,855)        221,474 (117,055--253,533)     0      n/a      0             n/a
   Tetanus                            5                       5,727,398               0.1%    1,145,480 (2,083,733)    244,849 (201,515--401,104)     0      n/a      0             n/a
   Trachoma                           6                       7,883,360               0.2%    1,313,893 (1,171,657)    977,242 (342,867--1,928,703)   4      0.32%    3,877,578     0.42%
   Tuberculosis                       413                     239,232,401             6.4%    579,255 (1,097,612)      226,748 (96,244--542,191)      83     6.74%    71,110,945    7.76%
   Varicella zoster virus             21                      4,721,860               0.0%    224,850 (281,832)        152,770 (50,883--243,513)      1      0.08%    177,901       0.02%

###### 

Years lived with disability (YLD) and 'investment by YLD observed' at three time points.

  Disease           YLD          Investment per YLD observed                                    
  ----------------- ------------ ----------------------------- ------------ --------- --------- ---------
  Campylobacter     746,000      746,000                       637,440      £2.10     £2.51     £3.51
  Chagas disease    308,932      303,000                       97,500       £1.61     £1.24     £3.39
  Chlamydia         632,136      669,000                       646,500      £3.64     £2.53     £2.50
  Cholera           80,000       80,000                        95,958       £0.21     £1.11     £0.75
  Dengue            9938         12,000                        565,900      £59.79    £308.03   £6.01
  Diphtheria        130          110                           100          £143.36   £104.26   £93.18
  *E. coli*         1,910,000    1,910,000                     1,624,445    £1.08     £1.08     £1.50
  Gonorrhoea        233,757      249,000                       225,400      £0.43     £0.26     £0.40
  Hepatitis A       182,394      185,000                       198,000      £0.64     £0.39     £0.29
  Hepatitis B       233,179      248,000                       172,600      £5.58     £3.90     £9.72
  Hepatitis C       36,450       39,000                        16,900       £136.61   £119.70   £407.76
  Hepatitis E       66,215       69,000                        56,600       £0.00     £0.00     £0.00
  HIV/AIDS          4,707,104    4,342,000                     4,063,700    £7.07     £8.57     £10.02
  Influenza         552,922      583,000                       115,225      £6.98     £10.93    £68.69
  Leishmaniasis     128,339      124,000                       49,700       £16.71    £25.52    £66.52
  Malaria           3,887,171    4,070,000                     3,170,500    £5.63     £6.95     £10.23
  Measles           59,444       31,000                        17,300       £7.06     £13.51    £43.35
  Meningitis        2,528,495    2,628,000                     1,679,100    £1.84     £1.55     £5.35
  Pertussis         149,225      122,000                       125,500      £1.42     £1.63     £3.33
  Pneumonia         572,838      604,000                       119,373      £2.56     £3.68     £46.03
  *Salmonella*      513,000      513,000                       438,668      £7.96     £8.66     £19.83
  Schistosomiasis   2,639,036    2,986,000                     2,861,700    £1.77     £1.12     £1.95
  Shigellosis       744,000      744,000                       596,315      £0.34     £0.37     £1.15
  Syphilis          89,379       91,000                        584,000      £1.11     £0.94     £0.24
  Tetanus           30,245       21,000                        13,200       £3.56     £20.98    £54.24
  Trypanosomiasis   10,742       80,000                        54,000       £386.71   £63.41    £190.48
  Tuberculosis      6,797,443    6,774,000                     3,669,700    £1.37     £1.83     £6.81
  Varicella         185,361      202,000                       197,200      £1.37     £1.73     £1.50
  Overall           28,033,875   28,425,110                    22,092,524   £28.37    £54.02    £87.58

###### 

Mortality and investment by mortality observed at three time points.

                          Number of deaths   Investment per mortality observed                                    
  ----------------------- ------------------ ----------------------------------- ----------- --------- ---------- ----------
  Campylobacter           163,092            109,000                             14,100      £10.50    £17.20     £158.67
  Chagas disease          11,000             10,300                              10,600      £48.61    £36.44     £31.16
  Chlamydia               9000               1200                                1100        £280.96   £1412.06   £1471.55
  Cholera                 86,932             58,100                              69,900      £0.22     £1.53      £1.03
  Clostridium difficile                                                          41,500                           £84.43
  Dengue                  18,000             14,700                              9100        £23.01    £251.46    £373.84
  Diphtheria              5000               2900                                3300        £3.61     £3.95      £2.82
  *E. coli*               313,465            209,500                             61,000      £7.31     £9.84      £39.94
  Gonorrhoea              1000               900                                 2300        £78.48    £72.03     £39.35
  Hepatitis A                                102,800                             14,900                £0.00      £0.00
  Hepatitis B             105,000            132,200                             68,600      £12.99    £7.32      £24.45
  Hepatitis C             54,000             16,000                              3500        £98.51    £291.77    £1968.88
  Hepatitis E                                56,600                              49,700                £0.00      £0.00
  HIV/AIDS                2,040,000          1,465,400                           1,341,000   £16.73    £25.39     £30.36
  Influenza               117,632            507,900                             105,400     £35.03    £12.55     £75.10
  Leishmaniasis           47,000             51,600                              62,500      £46.21    £61.33     £52.89
  Malaria                 889,000            1,169,500                           854,600     £25.94    £24.19     £37.94
  Measles                 424,000            125,400                             95,600      £0.65     £3.34      £7.85
  Meningitis              340,000            422,900                             303,500     £14.87    £9.65      £29.58
  Norovirus                                                                      1800                             £457.70
  Pertussis               254,000            81,400                              60,600      £0.96     £2.44      £6.90
  Pneumonia               1,235,381          1,460,700                           784,600     £1.33     £1.52      £7.00
  *Salmonella*            406,233            271,500                             239,300     £10.04    £16.37     £36.35
  Schistosomiasis         47,000             11,700                              5500        £109.01   £284.76    £1012.27
  Shigellosis             182,543            122,000                             73,900      £1.58     £2.25      £9.27
  Syphilis                99,000             113,300                             136,800     £1.15     £0.76      £1.02
  Tetanus                 163,000            61,300                              58,900      £0.76     £7.19      £12.15
  Trypanosomiasis         52,000             9100                                6900        £78.36    £557.48    £1490.69
  Tuberculosis            1,464,000          1,196,000                           1,290,300   £6.78     £10.35     £19.38
  Varicella                                  6800                                7000                             
  Overall                 8,527,278          7,790,700                           5,734,500   £85.28    £197.11    £337.39

###### 

Disability-adjusted life years (DALYs) and 'investment by DALY observed' at three time points.

                            DALYs         Cumulative investment per DALY observed                                 
  ------------------------- ------------- ----------------------------------------- ------------- ------- ------- --------
  Campylobacter             6,131,039     7,541,000                                 6,132,681     £0.28   £0.25   £0.36
  Chagas disease            429,872       546,000                                   338,000       £1.24   £0.69   £0.98
  Chlamydia                 3,748,198     714,000                                   692,000       £0.67   £2.37   £2.34
  Cholera                   3,628,541     4,463,000                                 3,629,512     £0.01   £0.02   £0.02
  *Clostridium difficile*                                                                                         
  Dengue                    669,647       825,000                                   1,142,000     £0.62   £4.48   £2.98
  Diphtheria                173,575       236,000                                   253,000       £0.10   £0.05   £0.04
  *E. coli*                 11,736,863    14,436,000                                11,740,005    £0.20   £0.14   £0.21
  Gonorrhoea                3,549,975     282,000                                   313,000       £0.02   £0.23   £0.29
  Hepatitis A                                                                       1,214,000                     £0.05
  Hepatitis B               2,067,533     4,674,000                                 2,587,000     £0.66   £0.21   £0.65
  Hepatitis C               954,622       518,000                                   138,000       £5.57   £9.01   £49.94
  Hepatitis E                                                                       2,616,000                     £0.00
  HIV/AIDS                  58,512,843    81,547,000                                69,363,000    £0.58   £0.46   £0.59
  Influenza                 15,784,216    19,244,000                                18,932,694    £0.26   £0.33   £0.42
  Leishmaniasis             1,974,465     3,317,000                                 4,283,000     £1.10   £0.95   £0.77
  Malaria                   33,976,025    82,685,000                                65,493,000    £0.68   £0.34   £0.50
  Measles                   14,852,775    10,420,000                                8,051,000     £0.02   £0.04   £0.09
  Meningitis                11,426,376    29,399,000                                21,014,000    £0.44   £0.14   £0.43
  Norovirus                                                                                                       
  Pertussis                 9,881,887     7,018,000                                 5,250,000     £0.02   £0.03   £0.08
  Pneumonia                 56,343,025    68,693,000                                67,581,770    £0.03   £0.03   £0.08
  *Salmonella*              13,891,385    17,086,000                                13,895,104    £0.29   £0.26   £0.63
  Schistosomiasis           1,707,143     3,309,000                                 3,062,000     £3.00   £1.01   £1.82
  Shigellosis               5,733,469     7,052,000                                 5,735,004     £0.05   £0.04   £0.12
  Syphilis                  2,846,113     9,578,000                                 11,324,000    £0.04   £0.01   £0.01
  Tetanus                   5,283,485     4,663,000                                 3,654,000     £0.02   £0.09   £0.20
  Trypanosomiasis           1,672,728     560,000                                   390,000       £2.44   £9.06   £26.37
  Tuberculosis              34,216,000    49,396,000                                49,816,000    £0.29   £0.25   £0.50
  Varicella                                                                         487,000                       £0.61
  Overall                   301,191,800   428,202,000                               379,126,770   £2.41   £3.59   £5.10

###### 

Rankings of research investment for 25 infectious diseases compared with 2013 YLD, mortality and DALYs.

  Disease           Research investment (UK pound) by burden observed, 2013             
  ----------------- --------------------------------------------------------- ---- ---- ----
  Hepatitis C       1.00                                                      1    1    1
  Trypanosomiasis   2.00                                                      2    2    2
  Leishmaniasis     6.67                                                      8    5    7
  Dengue            7.33                                                      5    14   3
  Influenza         8.33                                                      7    4    14
  Chlamydia         8.67                                                      3    19   4
  Schistosomiasis   9.67                                                      4    20   5
  *Salmonella*      10.00                                                     12   9    9
  Malaria           11.00                                                     11   10   12
  HIV/AIDS          11.67                                                     14   11   10
  Chagas Disease    12.00                                                     13   17   6
  Hepatitis B       12.00                                                     16   12   8
  Campylobacter     12.33                                                     6    16   15
  Tuberculosis      13.67                                                     17   13   11
  Tetanus           14.00                                                     18   6    18
  Meningitis        14.33                                                     15   15   13
  *E. coli*         15.67                                                     9    21   17
  Measles           16.00                                                     20   8    20
  Diphtheria        16.33                                                     23   3    23
  Pneumonia         16.33                                                     21   7    21
  Gonorrhoea        16.67                                                     10   24   16
  Shigellosis       20.00                                                     19   22   19
  Pertussis         20.67                                                     22   18   22
  Cholera           23.67                                                     24   23   24
  Syphilis          25.00                                                     25   25   25
