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Incidence of adult Huntington's disease in the UK: a UK-based primary care study and a systematic review

Incidence of adult Huntington's disease in the UK: a UK-based primary care study and a systematic... Open Access Research Incidence of adult Huntington’s disease in the UK: a UK-based primary care study and a systematic review 1,2 3 2 4 Nancy S Wexler, Laura Collett, Alice R Wexler, Michael D Rawlins, 5 4 4 3 Sarah J Tabrizi, Ian Douglas, Liam Smeeth, Stephen J Evans To cite: Wexler NS, Collett L, ABSTRACT Strengths and limitations of this study Wexler AR, et al. Incidence of Objectives: The prevalence of Huntington’s disease adult Huntington’s disease in (HD) recorded in the UK primary care records has ▪ The study provides the most reliable estimates of the UK: a UK-based primary increased twofold between 1990 and 2010. This the incidence of Huntington’s disease (HD), in care study and a systematic investigation was undertaken to assess whether this the UK, between 1990 and 2010. review. BMJ Open 2016;6: might be due to an increased incidence. We have also e009070. doi:10.1136/ ▪ The study also provides a comprehensive and undertaken a systematic review of published estimates bmjopen-2015-009070 contemporary review of the published incidence of the incidence of HD. of HD globally. Setting: Incident patients with a new diagnosis of HD ▪ The study of the incidence of HD in the UK relies Prepublication history and were identified from the primary care records of the on new diagnoses of HD being reported in additional material is Clinical Practice Research Datalink (CPRD). The available. To view please visit primary care records. systematic review included all published estimates of the journal (http://dx.doi.org/ ▪ The systematic review does not attempt a quanti- 10.1136/bmjopen-2015- the incidence of HD in defined populations. tative assessment of the quality of the included 009070). Participants: A total of 393 incident cases of HD studies. were identified from the CPRD database between 1990 Received 18 June 2015 and 2010 from a total population of 9 282 126 Revised 24 September 2015 persons. from 40 to 125 trinucleotide repeats. The Accepted 15 October 2015 Primary and secondary outcome measures: The HD gene codes for a protein called huntin- incidence of HD per million person-years was tin. The abnormal form of the gene codes estimated. From the systematic review, the extent of for a toxic protein. The gene can expand heterogeneity of published estimates of the incidence during transmission, possibly leading to dif- of HD was examined using the I statistic. ferent rates of incidence and prevalence in Results: The data showed that the incidence of HD different populations. has remained constant between 1990 and 2010 with HD usually presents in early to middle life an overall rate of 7.2 (95% CI 6.5 to 7.9) per million with abnormal movements including chorea, person-years. The systematic review identified 14 dystonia and rigidity. Patients may also independent estimates of incidence with substantial suffer severe psychiatric complications heterogeneity and consistently lower rates reported in including hallucinations, delusions, obsessive- studies from East Asia compared with those from Australia, North America and some—though not all— compulsive disorder, depression and bipolar those from Europe. Differences in incidence estimates disorder. They contend with progressive cog- did not appear to be explained solely by differences in nitive loss. It is uniformly fatal over a 10– case ascertainment or diagnostic methods. 20-year decline. Aspiration pneumonia and Conclusions: The rise in the prevalence of diagnosed suicide are common causes of death. HD in the UK, between 1990 and 2010, cannot be A previous study by us has shown that the attributed to an increase in incidence. Globally, prevalence of HD, as diagnosed and estimates of the incidence of HD show evidence of recorded in primary care records, has substantial heterogeneity with consistently lower rates increased from 5.4 (95% CI 3.8 to 7.5) per in East Asia and parts of Europe. Modifiers may play 100 000 in 1990 to 12.3 (95% CI 11.2 to an important role in determining the vulnerability of 13.5) per 100 000 in 2010. In order to different populations to expansions of the HD allele. explore the basis for this unexpected finding, we have undertaken a study of the For numbered affiliations see Huntington’s disease (HD) is an autosomal- incidence of HD in the UK over the same end of article. dominant neurological disorder. Located time period. on chromosome 4p16.3, the normal form of To place our own findings in context we Correspondence to the gene contains up to 38 trinucleotide have also undertaken a systematic review of Professor Michael D Rawlins; repeats. The abnormal form of the gene has michael.rawlins@nice.org.uk published estimates of the incidence of HD. Wexler NS, et al. BMJ Open 2016;6:e009070. doi:10.1136/bmjopen-2015-009070 1 Open Access A previous systematic review of the incidence (as well as The potential funders of the study played no part in prevalence) of HD was published in 2012 and identi- its design, analysis or interpretation. fied eight studies. That review only included studies carried out between 1985 and 2010 on the grounds that Participants and variables before 1985 MRI was not routinely in clinical use. Since The source population was all patients aged 21 years or the diagnosis of symptomatic (manifest) HD is essen- more who were registered with general practices contrib- tially a clinical one, and not dependent on imaging, the uting to the CPRD between 1990 and 2010. The age of present review attempted to identify all published esti- 21 was used to distinguish adult form of HD from the mates of the incidence of HD published between 1950 very rare juvenile form of the condition. Eligible cases and 2014. We sought to examine the heterogeneity were defined as persons with one or more recorded between these estimates and, in particular, the extent to diagnoses of HD or Huntington’s chorea in their which any observed differences between populations medical records. The Read codes used to identify cases might be explained by methods used for case finding of HD were F134.00 (Huntington’s chorea) and and diagnosis. Eu02200 (dementia in HD). For each general practice record, the observation period for the study began as the later of two dates: METHODS either the study start date (1 January 1990) or the date UK population-based estimates of the incidence of HD at which the practice started contributing research stand- Study design and setting ard data to the CPRD. The end of the observation The Clinical Practice Research Datalink (CPRD), for- period was the earlier of two dates: the last date for merly the General Practice Research Database (GPRD), which the practice contributed data to the CPRD, or the is a computerised database of anonymised longitudinal study end date (31 December 2010). Individual patients medical records from primary care that has been col- were included in denominators only during times within lected for over 25 years. The CPRD is assembled from the observation period that they were registered with a the electronic health records of patients registered with practice contributing data to the GPRD and were aged around 625 contributing general practices and with over at least 21 years. 5 million patients currently enrolled (representing Incident patients were defined as all those with a first approximately 8% of the UK population). The practices record of an HD diagnostic code, during the observa- are broadly representative of those in the UK in geo- tion period, but with two additional criteria. (1) The graphical distribution, practice size, age and sex as well patients’ first recorded HD diagnosis was required to as ethnicity and body mass index of registered patients. have occurred at least 12 months after their first entry in Each individual patient is assigned a unique identifica- the database. In other words, at least 12 months were tion number. No information from their medical required to have elapsed since their registration date. records, allowing identification of individual patients, is (2) Patients’ were required to have at least two recorded included in the database. The data are therefore entirely contacts with their contributing practice prior to their anonymous to investigators. It is also important to appre- HD diagnosis. These additional criteria helped avoid ciate, for the benefit of those unfamiliar with the UK’s including prevalent cases as if they were incident ones. National Health Service, that patients requiring specialist services must be referred by their general practitioner Statistical methods (GP). The referring GP will invariably be informed of Incidence was calculated from the ratio of number of the results of all investigations and the diagnosis. persons with a new recorded diagnosis of HD for each CPRD includes the complete diagnostic and prescrib- year from 1990 to 2010, divided by the total number of ing information for each registered patient. When persons in the database for that year, who had also had patients newly register with a contributing practice, at least 1 year in the database and were aged at least major past and existing diagnoses are recorded in their 21 years. Binomial CIs were calculated. In estimating the medical records and are included in the research data- incidence in age bands, annual incidence estimates were base. However, the dates of onset and of past diagnoses averaged and approximate (binomial) 95% CIs calcu- are not always accurately recorded. In particular, some lated. All incidence rates are expressed per million diagnoses that occurred in the past may be recorded person-years. without a date or as occurring at, or shortly after, the date of registration. Systematic review of studies of the incidence of HD Morbidity in UK primary care is recorded using Read The criteria for inclusion in the systematic review were codes Clinical Terms V.3. At both practice and individ- that a study should be based on a defined population ual patient levels, the data are subject to a range of and that it should provide information about the quality checks prior to being made available for research number of new HD diagnoses made within one or more purposes. The quality of the data has been found to be specific time frames. No study was excluded by virtue of high in a large number of independent validation its date, the ages studied, or because of the approach studies. taken to either case ascertainment or the diagnosis of 2 Wexler NS, et al. BMJ Open 2016;6:e009070. doi:10.1136/bmjopen-2015-009070 Open Access HD. The search dates covered the period January 1950 RESULTS to December 2013. There were no language restrictions. The incidence of adult HD in the UK Relevant publications were sought as follows: A total of 393 incident cases of HD were identified from 1. Search of MEDLINE and EMBASE (see web extra the CPRD database between 1990 and 2010 from a total annex 1). Studies fulfilling the inclusion criteria, but population of 9 282 126 persons (corresponding to published only as abstracts, were considered for 54 907 468 person-years). The incidence rates, in 5– inclusion. 6-year bands (table 1), showed no significant changes 2. Scrutiny of the references quoted in reviews of the between 1990 and 2010. The apparent fluctuations 10–17 epidemiology of HD. between 1990 and 1994 (see web extra annex 2) are 3. Examination of the reference lists in publications likely to be due to sampling error as both the number of meeting the inclusion criteria. incident cases, and the denominators, were relatively After the removal of duplicates, the full texts of the small during these years. The average incidence rate of remaining articles were examined. The relevant details HD, during the entire period, was 7.2 (95% CI 6.5 to of those meeting the inclusion criteria were transcribed 7.9) per million patient-years. Rates for females (7.1, independently (by ARW and MDR) and entered into 95% CI 6.1 to 8.10) and males (7.3, 95% CI 6.3 to 8.4) data extraction forms. Disagreements due to minor tran- were similar. scription errors were resolved by consensus. The data The mean age at diagnosis was 52.4 years (SD 15.1; extraction forms recorded: IQR 42–64 years; see figure 1). It was almost identical in ▸ The full reference; females (mean 52.4; SD 15.2; IQR 42–64 years) and ▸ The geographical location and year(s) of the study; males (52.4; SD 15.1; IQR 41–64 years). The ages of ▸ The relevant population size; onset are shown in table 1 and do not show any signifi- ▸ The number of patient-years used in the estimation cant change over the period of the study. The average (s) of incidence; annual incidence rates in relation to the age of onset ▸ The method(s) of case ascertainment; are shown in table 2. ▸ The method(s) of diagnosis; ▸ The number of new patients with HD during the year Systematic review of the incidence of HD (s) of study; The numbers of studies initially identified, screened, ▸ The mean age at diagnosis, where provided, of subjected to full-text review and included in the final patients with HD together with the age range or the synthesis are shown schematically in figure 1. Additional 95% CIs; details of the included and excluded in studies are avail- ▸ The estimate(s) of incidence with (if calculated) their able in the web extra tables 2–5. We identified 14 pub- 95% CIs. lished studies (figure 1) which, together with the results In some instances, where numerical data were lacking, of the present study, provided 15 investigations into the the number of patient-years was estimated by back incidence of HD for inclusion in our systematic review extrapolation. Where no 95% CIs were provided, these (table 3). were calculated from the available data. Reporting Estimates of the incidence of HD (table 3) ranged follows, where appropriate, the PRISMA guidelines. 20 from 0 (95% CI 0 to 97.0) to 8.0 (95% CI 2.0 to 23) per million person-years, although the latter study was con- ducted among a restricted age range (45–64 years). It is Statistical methods clear from this table that there is marked heterogeneity Incidence rates and their 95% CIs were recalculated (I =98.5%, 95% CI 98.2% to 98.6%) across studies, even 21 22 from the original reports from the number of new HD after the omission of the two age-specific estimates. diagnoses divided by the number of person-years. In Lower estimates of incidence were consistently reported some instances, where either the number of cases or the for studies conducted in the East Asia region including 20 23 24 number of person-years was not quoted, these were esti- Guam, Hong Kong and Taiwan compared with most mated by back extrapolation. The degree of heterogen- of those undertaken in Europe, North America and 2 19 eity was estimated from the I test. Australia. There is, though, heterogeneity between Table 1 Average incidence rates and age of onset of HD 1990–2010 Incident Denominators Incidence per million Mean age of onset Years cases (patient years) patient years (95% CIs) in years (SD and IQR) 1990–1996 56 6 778 613 8.26 (6.24 to 10.73) 51.5 (13.9 40 to 61) 1997–2003 138 18 533 173 7.45 (6.26 to 8.80) 53.1 (13.7 44 to 64) 2004–2010 199 29 522 583 6.7 (5.84 to 7.75) 52.1 (16.4 40 to 65) HD, Huntington’s disease. Wexler NS, et al. BMJ Open 2016;6:e009070. doi:10.1136/bmjopen-2015-009070 3 Open Access of possible explanations for the apparent rise in preva- lence. These included (1) an increase in incidence; (2) an increase in the diagnosis of HD as a result of the availability of a genetic test permitting physicians to diag- nose HD in patients with atypical symptoms; (3) an increase in the willingness of GPs to record a diagnosis of HD in patients’ records; (4) or an increase in the lon- gevity of those with manifest HD as a consequence of the general population trend as well as the result of better symptomatic treatment. Using the same database and during the same time period, our present study shows that the increase in prevalence of HD previously reported does not appear to be explained by a rise in incidence. More reliable diagnoses of HD are also unlikely to be an explanation because, if this had been the case, we should have observed an apparent increase in incidence. It is pos- sible that patients with a prior diagnosis of HD are more likely to register with a practice contributing to the Figure 1 Flow diagram of search strategy. CPRD. We doubt that this is a viable explanation and, anyway, it should also be reflected by an increased European estimates of incidence. Studies conducted in incidence. 25 26 27 Finland, Iceland and the Ferrara region of Italy There are two remaining possibilities for this surpris- show incidence estimates of around one per million ing rise in prevalence in the face of a constant inci- 21 28 person-years or less. Other studies carried out in UK, dence: (1) GPs are now more willing to include an HD as well as the results reported here, suggest incidence diagnosis in the records of previously diagnosed patients rates of around 7–8 per million patient years (table 4). potentially due to a decline in the stigma associated with Estimates undertaken in Greece, the Basque region of the condition ; (2) survival has markedly improved. We 30 31 32 33 Spain, Australia and North America are compar- are currently examining this second possibility. able to those in the UK including the present study. The low incidence of the juvenile form of HD, in the UK, is to be expected in the light of the known low prevalence Systematic review of incidence of this very rare form of HD. The present systematic review confirms the apparent het- The approaches used in case ascertainment, and the erogeneity of the incidence of HD between different criteria for accepting a diagnosis of HD among the populations. Studies undertaken in Eastern Asia show included studies, are shown in table 4. A variety of consistently lower estimates of incidence compared with methods were used in identifying patients with HD and, those reported from Australasia, North America and to a lesser extent, in the diagnostic criteria each study parts of Europe. It is notable, however, that substantial adopted. However, this variability is inadequate to heterogeneity in the incidence of HD has been reported explain the marked differences in the heterogeneity of in the European region with, as already discussed, esti- incidence worldwide. mates from Finland, Iceland and Northern Italy being substantially less than those reported in Spain and the UK (table 3). DISCUSSION Although it is possible that this observed heterogeneity UK estimate of incidence in the estimates of the incidence of HD could be due to The absence of any consistent change in the incidence differences in the methodology of case ascertainment of HD in the UK, between 1990 and 2010, is in marked and diagnosis, examination of the data in table 4 sug- contrast to the substantial increase in the prevalence of gests that this is unlikely to be the sole explanation. HD over the same period. Evans et al offered a number Indeed, the heterogeneity of the estimates of the Table 2 Incidence and age of onset Incidence per million patient years (95% CIs) Age of onset (years) 1990–1996 1997–2003 2004–2010 <40 7.9 (4.4 to 13.1) 5.6 (3.7 to 8.1) 6.6 (4.9 to 8.7) 40–49 13.2 (7.0 to 22.6) 11.8 (8.0 to 16.8) 10.8 (8.0 to 14.3) 50–59 14.8 (7.6, 25.8) 13.1 (9.0 to 18.4) 7.2 (4.8 to 10.4) >60 10.0 (5.7 to 16.2) 10.7 (7.8 to 14.3) 10.3 (8.1 to 13.0) 4 Wexler NS, et al. BMJ Open 2016;6:e009070. doi:10.1136/bmjopen-2015-009070 Open Access Wexler NS, et al. BMJ Open 2016;6:e009070. doi:10.1136/bmjopen-2015-009070 5 Table 3 Incidence studies from the systematic review Study year Incident Incidence per 1 000 000 Study ID Location (s) cases Patient-years person-years (95% CIs) Age of onset Comments Eastern Asia Chen 1968 Guam 1960–1966 0 265 825 0.00 (0 to 13.9) Not stated Chang 1994 Hong Kong, 1984–1991 20 43 520 000 0.46 (0.28 to 0.71)* 37.6 (range 20–52) China Chen 2010 Taiwan 2000–2007 165 15 900 000 1.04 (0.89 to 1.21) Not stated Average incidence between 2000 and Australasia McCusker 2000 NSW, Australia 1991 and 1991=26 1991=5 732 031 1991=4.5 (3.0 to 6.7) 47.9 1996 1996=39 1996=6 038 969 1996=6.5 (4.6 to 8.8) (SD 13.7) Europe Palo 1987 Finland 1980s 2† 4 900 000 0.2 to 0.4 (0.02 to 1.3)* Not stated Govoni 1988 Ferrara, Italy 1971–1987 14 6 032 096‡ 1.1 (0.4 to 2.3) Not stated Ramos-Arroyo 2005 Navara and 1994–2002 111 21 165 000 4.7 (4.5 to 6.3)* 43.7 Basque, Spain (SD 15) Mercy 2008 Cambridge UK 2000–2006 9 453 600 8.0 (2.0 to 23) Not stated Restricted age range (45–64 years) Panas 2011 Greece 1995–2008 48† 10 964 020 4.38 (3.23 to 5.50) 44.0 (SD 12.9) Sackley 2011 UK 2004–2008 85 14 713 708 5.71 (4.45 to 7.07) 48.3 (SD14.) Average incidence between 2004 and Sveinsson 2012 Iceland 1988–2007 8 5 714 285‡ 1.4 (0.6 to 2.8)* 51 (range 28–68) Douglas 2013 UK 1990–2010 12 17 142 857 0.70 (0.36 to 1.22) Median=15 (range Restricted to juvenile 5–20) HD Current study UK 1990–2010 393 54 907 468 7.2 (6.5 to 7.9) 52 years (SD 16) Also includes annual incidence rates1990– North America Kokman 1994 Minnesota, USA 1950–1989 10 4 134 000‡ Definite=3.0 (1.0 to 5.0) Not stated . Definite+probability=5.0 (3.0 to 9.0) Almqvist 2001 British 1996–1999 110 16 058 394‡ 6.9 (5.7 to 8.3)* 46.9 (SD 13.7) Author states Columbia, population is Canada ‘approximate’ *95% CIs not included in the published report but estimated for this review. †Numbers of patients with HD calculated by back extrapolation. ‡Patient-years calculated by back extrapolation. HD, Huntington’s disease; NSW, New South Wales. Open Access Table 4 Sources of cases and diagnostic criteria used in the included studies Study ID Location Source of cases Diagnostic criteria Asia Chen 1968 Guam Records of patients attending the Not stated Guam Memorial Hospital Chang 1994 Hong Kong, Computer search of all major All patients examined by a neurologist China hospitals. Announcement in Hong plus a psychiatrist. Diagnosis based on Kong Medical Association Newsletter positive family history plus insidious asking for information about known or progressive disorder with chorea, suspected cases. Enquiry of all cognitive impairment and often neurologists and psychiatrists in Hong psychiatric disturbance. Positive CT Kong scan with caudate atrophy considered to be ‘supportive’ of an HD diagnosis Chen 2010 Taiwan Outpatient and inpatient claims from Search of National Health Insurance the National Health Insurance Research Database for ICD-9 code Research Database 333.4 Australasia McCusker 2000 NSW, Records of the NSW HD Service. Definite: chorea or ataxia with a Australia Records of the major general and positive family history or expanded chronic psychiatric hospitals in NSW. CAG repeat Questionnaires to adult and paediatric neurologists, psychiatrists, genetic counsellors and clinical geneticists Europe Palo 1987 Finland Systematic search of all university, Not stated central, general and central psychiatric hospitals Govoni 1988 Ferrara, Italy Records of the neurology clinics of Combination of a positive family Ferrera and Bologna, civil records, history, choreiform movements, mental records of the psychiatric institutions, deterioration records of public and private geriatric nursing homes Ramos-Arroyo 2005 Navara and Referrals to the Medical Genetics Definite=typical clinical features plus Basque, Spain Laboratory of the Hospital Virgen del <36 CAG repeats plus positive family Camino, Pamplona, Spain, for history diagnostic testing for HD between Suspect=without positive family history 1993 and 2002. Also searched for additional patients from the Basque country who might have been referred to other HD diagnostic genetic centres in Spain. In addition, patients who underwent presymptomatic testing and became symptomatic within the study period were also included Mercy 2008 Cambridge Attendees/referrals to Addenbrooks’ UHDRS >5 UK Hospital memory/early dementia clinic Panas 2011 Greece Records of the Laboratory of Neurological examination including the Neurogenetics, Athens (the only UHDRS plus CAG repeat length in a neurogenetics lab in Greece) subset of patients Sackley 2011 UK Using THIN primary care research Based on recorded diagnosis database the authors identified Read codes for HD Sveinsson 2012 Iceland Medical records and hospital Hyperkinetic movement disorder plus discharge diagnoses of all hospitals psychiatric symptoms plus progressive including records of neurological, cognitive decline plus a positive family psychiatric and genetic departments. history or positive DNA analysis Information from practising neurologists and selected GPs. Information from family members Continued 6 Wexler NS, et al. BMJ Open 2016;6:e009070. doi:10.1136/bmjopen-2015-009070 Open Access Table 4 Continued Study ID Location Source of cases Diagnostic criteria Douglas 2013 UK Primary care National Health Service As recorded in patients’ electronic electronic health records health records (Read codes F134.00 and Eu2200) Current study UK Primary care National Health Service As recorded in patients’ electronic electronic health records health records (Read codes F134.00 and Eu2200) North America Kokman 1994 Minnesota, Scrutiny of records of hospitals, Definite HD=documented record of USA nursing homes, private practitioners, progressive choreiform movement state psychiatric hospital disorder; evidence of autosomal dominant inheritance; progressive cognitive, behavioural, and/or emotional dysfunction. Probable HD=2 out of 3 of the above criteria Almqvist 2001 British Patients referred to Medical Genetics Patients with signs and symptoms Columbia, Laboratory/HD clinic compatible with HD and with CAG Canada repeat lengths >36 HD, Huntington’s disease; GP, general practitioner; ICD, International Classification of Diseases; NSW, New South Wales; THIN, The Health Improvement Network; UHDRS, United Huntington’s Disease Rating Scale. incidence of HD is broadly consistent with the hetero- in different populations, may help to develop new thera- geneity of estimates of the prevalence of the condition. peutic strategies. Lower prevalence rates of HD have been noted in studies carried out in Asia compared with those among Author affiliations Department of Neurology and Psychiatry, Columbia University, New York, populations predominantly of European decent. The New York, USA estimates of incidence among Finish and Icelandic Hereditary Disease Foundation, New York, New York, USA peoples as well as Italians from the Ferrara region of 3 Department of Medical Statistics, London School of Hygiene and Tropical Italy are also compatible with the low prevalence rates in Medicine, London, UK these populations. The very low incidence of juvenile Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK HD, in the UK (0.70, 95% CI 0.36 to 1.22 per million Department of Neurodegenerative Diseases, Institute of Neurology, University person-years), is also consistent with its low prevalence College London, London, UK (6.77, 95%CI 5.6 to 8.12 per million) compared with the most recent (2010) estimate of the prevalence of adult Contributors All the authors contributed to the design of the study. Data extraction from CPRD was undertaken by LC, ID, SJE and LS. Data analyses HD (123, 95% CI 112 to 135 per million). were performed by LC, NSW and MDR. Statistical analyses were performed by Adefinitive molecular genetic test for the HD muta- LC, SJE and MDR. The systematic review was undertaken by ARW and MDR. tion has been available since the early 1990s in most All authors contributed to, and approved, the submitted manuscript. developed countries. Differences in the rates of genetic Funding The authors gratefully acknowledge support for this study from the testing might provide some explanation for the differ- Hereditary Disease Foundation, the Wellcome Trust and the Medical Research ences in the heterogeneity of estimates of incidence in Council. the populations studied. This explanation also seems Competing interests None declared. unlikely. For example, the overall incidence of HD in Ethics approval The study was approved from the CPRD’s Independent Taiwan, during the past decade, has remained consist- Scientific Advisory Committee and from the London School of Hygiene and ently lower than estimates from the UK over similar time Tropical Medicine’s Research Ethics Committee. periods. Provenance and peer review Not commissioned; externally peer reviewed. The present study suggests that, over the past two decades, the incidence of HD in the UK has remained Data sharing statement No additional data are available. constant despite a doubling of the prevalence of HD Open Access This is an Open Access article distributed in accordance with during this same time period. We also demonstrate that the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for there is significant heterogeneity in the estimates of the commercial use, provided the original work is properly cited. See: http:// incidence of HD carried out in other populations world- creativecommons.org/licenses/by/4.0/ wide. Particularly low estimates of incidence in Eastern Asia, as well as parts of Europe, suggests that modifiers of the expression of the disease may play an important REFERENCES role in determining the propensity of populations to be 1. Novak MJ, Tabrizi SJ. Huntington’s disease. BMJ 2010;341:34–40. vulnerable to expansions of the HD allele. Better 2. Wexler NS. Huntington’s disease: advocacy driving science. Annu understanding of the potential modifiers of expression, Rev Med 2012;63:1–22. Wexler NS, et al. BMJ Open 2016;6:e009070. doi:10.1136/bmjopen-2015-009070 7 Open Access 3. 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Almqvist EW, Elterman DS, MacLeod PM, et al. High incidence rate 16. Centre for Molecular Medicine and Therapeutics. Published reports and absent family histories in one quarter of patients newly of the worldwide prevalence of Huntington’s disease. University of diagnosed with Huntington disease in British Columbia. Clin Genet British Columbia, 2011. 2001;60:198–205. 17. http://www.cmmt.ubc.ca/research/diseases/huntingtons/HD_ 34. Wexler AR. The woman who walked into the sea: Huntington’s and Prevalence (accessed 9 Jun 2015). the making of a genetic disease. New Haven: Yale University Press, 18. Moher D, Liberati A, Tetzlaff J, et al., The PRISMA Group. Preferred 2008. Reporting Items for Systematic Reviews and Meta-Analyses: the 35. Warby SC, Visscher H, Collins JA, et al. HTT haplotypes contribute PRISMA statement. PLoS Med 2009;6:e1000097. to differences in Huntington disease prevalence between Europe 19. Higgins JP, Thompson SG, Deeks JJ, et al. and East Asia. Eur J Hum Genet 2011;19:561–6. Measuring inconsistency in meta-analysis. BMJ 2003; 36. Xu M, Wu ZY. Huntington disease in Asia. Chin Med J (Engl) 327:557–60. 2015;128:1815–19. 8 Wexler NS, et al. BMJ Open 2016;6:e009070. doi:10.1136/bmjopen-2015-009070 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMJ Open British Medical Journal

Incidence of adult Huntington's disease in the UK: a UK-based primary care study and a systematic review

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Open Access Research Incidence of adult Huntington’s disease in the UK: a UK-based primary care study and a systematic review 1,2 3 2 4 Nancy S Wexler, Laura Collett, Alice R Wexler, Michael D Rawlins, 5 4 4 3 Sarah J Tabrizi, Ian Douglas, Liam Smeeth, Stephen J Evans To cite: Wexler NS, Collett L, ABSTRACT Strengths and limitations of this study Wexler AR, et al. Incidence of Objectives: The prevalence of Huntington’s disease adult Huntington’s disease in (HD) recorded in the UK primary care records has ▪ The study provides the most reliable estimates of the UK: a UK-based primary increased twofold between 1990 and 2010. This the incidence of Huntington’s disease (HD), in care study and a systematic investigation was undertaken to assess whether this the UK, between 1990 and 2010. review. BMJ Open 2016;6: might be due to an increased incidence. We have also e009070. doi:10.1136/ ▪ The study also provides a comprehensive and undertaken a systematic review of published estimates bmjopen-2015-009070 contemporary review of the published incidence of the incidence of HD. of HD globally. Setting: Incident patients with a new diagnosis of HD ▪ The study of the incidence of HD in the UK relies Prepublication history and were identified from the primary care records of the on new diagnoses of HD being reported in additional material is Clinical Practice Research Datalink (CPRD). The available. To view please visit primary care records. systematic review included all published estimates of the journal (http://dx.doi.org/ ▪ The systematic review does not attempt a quanti- 10.1136/bmjopen-2015- the incidence of HD in defined populations. tative assessment of the quality of the included 009070). Participants: A total of 393 incident cases of HD studies. were identified from the CPRD database between 1990 Received 18 June 2015 and 2010 from a total population of 9 282 126 Revised 24 September 2015 persons. from 40 to 125 trinucleotide repeats. The Accepted 15 October 2015 Primary and secondary outcome measures: The HD gene codes for a protein called huntin- incidence of HD per million person-years was tin. The abnormal form of the gene codes estimated. From the systematic review, the extent of for a toxic protein. The gene can expand heterogeneity of published estimates of the incidence during transmission, possibly leading to dif- of HD was examined using the I statistic. ferent rates of incidence and prevalence in Results: The data showed that the incidence of HD different populations. has remained constant between 1990 and 2010 with HD usually presents in early to middle life an overall rate of 7.2 (95% CI 6.5 to 7.9) per million with abnormal movements including chorea, person-years. The systematic review identified 14 dystonia and rigidity. Patients may also independent estimates of incidence with substantial suffer severe psychiatric complications heterogeneity and consistently lower rates reported in including hallucinations, delusions, obsessive- studies from East Asia compared with those from Australia, North America and some—though not all— compulsive disorder, depression and bipolar those from Europe. Differences in incidence estimates disorder. They contend with progressive cog- did not appear to be explained solely by differences in nitive loss. It is uniformly fatal over a 10– case ascertainment or diagnostic methods. 20-year decline. Aspiration pneumonia and Conclusions: The rise in the prevalence of diagnosed suicide are common causes of death. HD in the UK, between 1990 and 2010, cannot be A previous study by us has shown that the attributed to an increase in incidence. Globally, prevalence of HD, as diagnosed and estimates of the incidence of HD show evidence of recorded in primary care records, has substantial heterogeneity with consistently lower rates increased from 5.4 (95% CI 3.8 to 7.5) per in East Asia and parts of Europe. Modifiers may play 100 000 in 1990 to 12.3 (95% CI 11.2 to an important role in determining the vulnerability of 13.5) per 100 000 in 2010. In order to different populations to expansions of the HD allele. explore the basis for this unexpected finding, we have undertaken a study of the For numbered affiliations see Huntington’s disease (HD) is an autosomal- incidence of HD in the UK over the same end of article. dominant neurological disorder. Located time period. on chromosome 4p16.3, the normal form of To place our own findings in context we Correspondence to the gene contains up to 38 trinucleotide have also undertaken a systematic review of Professor Michael D Rawlins; repeats. The abnormal form of the gene has michael.rawlins@nice.org.uk published estimates of the incidence of HD. Wexler NS, et al. BMJ Open 2016;6:e009070. doi:10.1136/bmjopen-2015-009070 1 Open Access A previous systematic review of the incidence (as well as The potential funders of the study played no part in prevalence) of HD was published in 2012 and identi- its design, analysis or interpretation. fied eight studies. That review only included studies carried out between 1985 and 2010 on the grounds that Participants and variables before 1985 MRI was not routinely in clinical use. Since The source population was all patients aged 21 years or the diagnosis of symptomatic (manifest) HD is essen- more who were registered with general practices contrib- tially a clinical one, and not dependent on imaging, the uting to the CPRD between 1990 and 2010. The age of present review attempted to identify all published esti- 21 was used to distinguish adult form of HD from the mates of the incidence of HD published between 1950 very rare juvenile form of the condition. Eligible cases and 2014. We sought to examine the heterogeneity were defined as persons with one or more recorded between these estimates and, in particular, the extent to diagnoses of HD or Huntington’s chorea in their which any observed differences between populations medical records. The Read codes used to identify cases might be explained by methods used for case finding of HD were F134.00 (Huntington’s chorea) and and diagnosis. Eu02200 (dementia in HD). For each general practice record, the observation period for the study began as the later of two dates: METHODS either the study start date (1 January 1990) or the date UK population-based estimates of the incidence of HD at which the practice started contributing research stand- Study design and setting ard data to the CPRD. The end of the observation The Clinical Practice Research Datalink (CPRD), for- period was the earlier of two dates: the last date for merly the General Practice Research Database (GPRD), which the practice contributed data to the CPRD, or the is a computerised database of anonymised longitudinal study end date (31 December 2010). Individual patients medical records from primary care that has been col- were included in denominators only during times within lected for over 25 years. The CPRD is assembled from the observation period that they were registered with a the electronic health records of patients registered with practice contributing data to the GPRD and were aged around 625 contributing general practices and with over at least 21 years. 5 million patients currently enrolled (representing Incident patients were defined as all those with a first approximately 8% of the UK population). The practices record of an HD diagnostic code, during the observa- are broadly representative of those in the UK in geo- tion period, but with two additional criteria. (1) The graphical distribution, practice size, age and sex as well patients’ first recorded HD diagnosis was required to as ethnicity and body mass index of registered patients. have occurred at least 12 months after their first entry in Each individual patient is assigned a unique identifica- the database. In other words, at least 12 months were tion number. No information from their medical required to have elapsed since their registration date. records, allowing identification of individual patients, is (2) Patients’ were required to have at least two recorded included in the database. The data are therefore entirely contacts with their contributing practice prior to their anonymous to investigators. It is also important to appre- HD diagnosis. These additional criteria helped avoid ciate, for the benefit of those unfamiliar with the UK’s including prevalent cases as if they were incident ones. National Health Service, that patients requiring specialist services must be referred by their general practitioner Statistical methods (GP). The referring GP will invariably be informed of Incidence was calculated from the ratio of number of the results of all investigations and the diagnosis. persons with a new recorded diagnosis of HD for each CPRD includes the complete diagnostic and prescrib- year from 1990 to 2010, divided by the total number of ing information for each registered patient. When persons in the database for that year, who had also had patients newly register with a contributing practice, at least 1 year in the database and were aged at least major past and existing diagnoses are recorded in their 21 years. Binomial CIs were calculated. In estimating the medical records and are included in the research data- incidence in age bands, annual incidence estimates were base. However, the dates of onset and of past diagnoses averaged and approximate (binomial) 95% CIs calcu- are not always accurately recorded. In particular, some lated. All incidence rates are expressed per million diagnoses that occurred in the past may be recorded person-years. without a date or as occurring at, or shortly after, the date of registration. Systematic review of studies of the incidence of HD Morbidity in UK primary care is recorded using Read The criteria for inclusion in the systematic review were codes Clinical Terms V.3. At both practice and individ- that a study should be based on a defined population ual patient levels, the data are subject to a range of and that it should provide information about the quality checks prior to being made available for research number of new HD diagnoses made within one or more purposes. The quality of the data has been found to be specific time frames. No study was excluded by virtue of high in a large number of independent validation its date, the ages studied, or because of the approach studies. taken to either case ascertainment or the diagnosis of 2 Wexler NS, et al. BMJ Open 2016;6:e009070. doi:10.1136/bmjopen-2015-009070 Open Access HD. The search dates covered the period January 1950 RESULTS to December 2013. There were no language restrictions. The incidence of adult HD in the UK Relevant publications were sought as follows: A total of 393 incident cases of HD were identified from 1. Search of MEDLINE and EMBASE (see web extra the CPRD database between 1990 and 2010 from a total annex 1). Studies fulfilling the inclusion criteria, but population of 9 282 126 persons (corresponding to published only as abstracts, were considered for 54 907 468 person-years). The incidence rates, in 5– inclusion. 6-year bands (table 1), showed no significant changes 2. Scrutiny of the references quoted in reviews of the between 1990 and 2010. The apparent fluctuations 10–17 epidemiology of HD. between 1990 and 1994 (see web extra annex 2) are 3. Examination of the reference lists in publications likely to be due to sampling error as both the number of meeting the inclusion criteria. incident cases, and the denominators, were relatively After the removal of duplicates, the full texts of the small during these years. The average incidence rate of remaining articles were examined. The relevant details HD, during the entire period, was 7.2 (95% CI 6.5 to of those meeting the inclusion criteria were transcribed 7.9) per million patient-years. Rates for females (7.1, independently (by ARW and MDR) and entered into 95% CI 6.1 to 8.10) and males (7.3, 95% CI 6.3 to 8.4) data extraction forms. Disagreements due to minor tran- were similar. scription errors were resolved by consensus. The data The mean age at diagnosis was 52.4 years (SD 15.1; extraction forms recorded: IQR 42–64 years; see figure 1). It was almost identical in ▸ The full reference; females (mean 52.4; SD 15.2; IQR 42–64 years) and ▸ The geographical location and year(s) of the study; males (52.4; SD 15.1; IQR 41–64 years). The ages of ▸ The relevant population size; onset are shown in table 1 and do not show any signifi- ▸ The number of patient-years used in the estimation cant change over the period of the study. The average (s) of incidence; annual incidence rates in relation to the age of onset ▸ The method(s) of case ascertainment; are shown in table 2. ▸ The method(s) of diagnosis; ▸ The number of new patients with HD during the year Systematic review of the incidence of HD (s) of study; The numbers of studies initially identified, screened, ▸ The mean age at diagnosis, where provided, of subjected to full-text review and included in the final patients with HD together with the age range or the synthesis are shown schematically in figure 1. Additional 95% CIs; details of the included and excluded in studies are avail- ▸ The estimate(s) of incidence with (if calculated) their able in the web extra tables 2–5. We identified 14 pub- 95% CIs. lished studies (figure 1) which, together with the results In some instances, where numerical data were lacking, of the present study, provided 15 investigations into the the number of patient-years was estimated by back incidence of HD for inclusion in our systematic review extrapolation. Where no 95% CIs were provided, these (table 3). were calculated from the available data. Reporting Estimates of the incidence of HD (table 3) ranged follows, where appropriate, the PRISMA guidelines. 20 from 0 (95% CI 0 to 97.0) to 8.0 (95% CI 2.0 to 23) per million person-years, although the latter study was con- ducted among a restricted age range (45–64 years). It is Statistical methods clear from this table that there is marked heterogeneity Incidence rates and their 95% CIs were recalculated (I =98.5%, 95% CI 98.2% to 98.6%) across studies, even 21 22 from the original reports from the number of new HD after the omission of the two age-specific estimates. diagnoses divided by the number of person-years. In Lower estimates of incidence were consistently reported some instances, where either the number of cases or the for studies conducted in the East Asia region including 20 23 24 number of person-years was not quoted, these were esti- Guam, Hong Kong and Taiwan compared with most mated by back extrapolation. The degree of heterogen- of those undertaken in Europe, North America and 2 19 eity was estimated from the I test. Australia. There is, though, heterogeneity between Table 1 Average incidence rates and age of onset of HD 1990–2010 Incident Denominators Incidence per million Mean age of onset Years cases (patient years) patient years (95% CIs) in years (SD and IQR) 1990–1996 56 6 778 613 8.26 (6.24 to 10.73) 51.5 (13.9 40 to 61) 1997–2003 138 18 533 173 7.45 (6.26 to 8.80) 53.1 (13.7 44 to 64) 2004–2010 199 29 522 583 6.7 (5.84 to 7.75) 52.1 (16.4 40 to 65) HD, Huntington’s disease. Wexler NS, et al. BMJ Open 2016;6:e009070. doi:10.1136/bmjopen-2015-009070 3 Open Access of possible explanations for the apparent rise in preva- lence. These included (1) an increase in incidence; (2) an increase in the diagnosis of HD as a result of the availability of a genetic test permitting physicians to diag- nose HD in patients with atypical symptoms; (3) an increase in the willingness of GPs to record a diagnosis of HD in patients’ records; (4) or an increase in the lon- gevity of those with manifest HD as a consequence of the general population trend as well as the result of better symptomatic treatment. Using the same database and during the same time period, our present study shows that the increase in prevalence of HD previously reported does not appear to be explained by a rise in incidence. More reliable diagnoses of HD are also unlikely to be an explanation because, if this had been the case, we should have observed an apparent increase in incidence. It is pos- sible that patients with a prior diagnosis of HD are more likely to register with a practice contributing to the Figure 1 Flow diagram of search strategy. CPRD. We doubt that this is a viable explanation and, anyway, it should also be reflected by an increased European estimates of incidence. Studies conducted in incidence. 25 26 27 Finland, Iceland and the Ferrara region of Italy There are two remaining possibilities for this surpris- show incidence estimates of around one per million ing rise in prevalence in the face of a constant inci- 21 28 person-years or less. Other studies carried out in UK, dence: (1) GPs are now more willing to include an HD as well as the results reported here, suggest incidence diagnosis in the records of previously diagnosed patients rates of around 7–8 per million patient years (table 4). potentially due to a decline in the stigma associated with Estimates undertaken in Greece, the Basque region of the condition ; (2) survival has markedly improved. We 30 31 32 33 Spain, Australia and North America are compar- are currently examining this second possibility. able to those in the UK including the present study. The low incidence of the juvenile form of HD, in the UK, is to be expected in the light of the known low prevalence Systematic review of incidence of this very rare form of HD. The present systematic review confirms the apparent het- The approaches used in case ascertainment, and the erogeneity of the incidence of HD between different criteria for accepting a diagnosis of HD among the populations. Studies undertaken in Eastern Asia show included studies, are shown in table 4. A variety of consistently lower estimates of incidence compared with methods were used in identifying patients with HD and, those reported from Australasia, North America and to a lesser extent, in the diagnostic criteria each study parts of Europe. It is notable, however, that substantial adopted. However, this variability is inadequate to heterogeneity in the incidence of HD has been reported explain the marked differences in the heterogeneity of in the European region with, as already discussed, esti- incidence worldwide. mates from Finland, Iceland and Northern Italy being substantially less than those reported in Spain and the UK (table 3). DISCUSSION Although it is possible that this observed heterogeneity UK estimate of incidence in the estimates of the incidence of HD could be due to The absence of any consistent change in the incidence differences in the methodology of case ascertainment of HD in the UK, between 1990 and 2010, is in marked and diagnosis, examination of the data in table 4 sug- contrast to the substantial increase in the prevalence of gests that this is unlikely to be the sole explanation. HD over the same period. Evans et al offered a number Indeed, the heterogeneity of the estimates of the Table 2 Incidence and age of onset Incidence per million patient years (95% CIs) Age of onset (years) 1990–1996 1997–2003 2004–2010 <40 7.9 (4.4 to 13.1) 5.6 (3.7 to 8.1) 6.6 (4.9 to 8.7) 40–49 13.2 (7.0 to 22.6) 11.8 (8.0 to 16.8) 10.8 (8.0 to 14.3) 50–59 14.8 (7.6, 25.8) 13.1 (9.0 to 18.4) 7.2 (4.8 to 10.4) >60 10.0 (5.7 to 16.2) 10.7 (7.8 to 14.3) 10.3 (8.1 to 13.0) 4 Wexler NS, et al. BMJ Open 2016;6:e009070. doi:10.1136/bmjopen-2015-009070 Open Access Wexler NS, et al. BMJ Open 2016;6:e009070. doi:10.1136/bmjopen-2015-009070 5 Table 3 Incidence studies from the systematic review Study year Incident Incidence per 1 000 000 Study ID Location (s) cases Patient-years person-years (95% CIs) Age of onset Comments Eastern Asia Chen 1968 Guam 1960–1966 0 265 825 0.00 (0 to 13.9) Not stated Chang 1994 Hong Kong, 1984–1991 20 43 520 000 0.46 (0.28 to 0.71)* 37.6 (range 20–52) China Chen 2010 Taiwan 2000–2007 165 15 900 000 1.04 (0.89 to 1.21) Not stated Average incidence between 2000 and Australasia McCusker 2000 NSW, Australia 1991 and 1991=26 1991=5 732 031 1991=4.5 (3.0 to 6.7) 47.9 1996 1996=39 1996=6 038 969 1996=6.5 (4.6 to 8.8) (SD 13.7) Europe Palo 1987 Finland 1980s 2† 4 900 000 0.2 to 0.4 (0.02 to 1.3)* Not stated Govoni 1988 Ferrara, Italy 1971–1987 14 6 032 096‡ 1.1 (0.4 to 2.3) Not stated Ramos-Arroyo 2005 Navara and 1994–2002 111 21 165 000 4.7 (4.5 to 6.3)* 43.7 Basque, Spain (SD 15) Mercy 2008 Cambridge UK 2000–2006 9 453 600 8.0 (2.0 to 23) Not stated Restricted age range (45–64 years) Panas 2011 Greece 1995–2008 48† 10 964 020 4.38 (3.23 to 5.50) 44.0 (SD 12.9) Sackley 2011 UK 2004–2008 85 14 713 708 5.71 (4.45 to 7.07) 48.3 (SD14.) Average incidence between 2004 and Sveinsson 2012 Iceland 1988–2007 8 5 714 285‡ 1.4 (0.6 to 2.8)* 51 (range 28–68) Douglas 2013 UK 1990–2010 12 17 142 857 0.70 (0.36 to 1.22) Median=15 (range Restricted to juvenile 5–20) HD Current study UK 1990–2010 393 54 907 468 7.2 (6.5 to 7.9) 52 years (SD 16) Also includes annual incidence rates1990– North America Kokman 1994 Minnesota, USA 1950–1989 10 4 134 000‡ Definite=3.0 (1.0 to 5.0) Not stated . Definite+probability=5.0 (3.0 to 9.0) Almqvist 2001 British 1996–1999 110 16 058 394‡ 6.9 (5.7 to 8.3)* 46.9 (SD 13.7) Author states Columbia, population is Canada ‘approximate’ *95% CIs not included in the published report but estimated for this review. †Numbers of patients with HD calculated by back extrapolation. ‡Patient-years calculated by back extrapolation. HD, Huntington’s disease; NSW, New South Wales. Open Access Table 4 Sources of cases and diagnostic criteria used in the included studies Study ID Location Source of cases Diagnostic criteria Asia Chen 1968 Guam Records of patients attending the Not stated Guam Memorial Hospital Chang 1994 Hong Kong, Computer search of all major All patients examined by a neurologist China hospitals. Announcement in Hong plus a psychiatrist. Diagnosis based on Kong Medical Association Newsletter positive family history plus insidious asking for information about known or progressive disorder with chorea, suspected cases. Enquiry of all cognitive impairment and often neurologists and psychiatrists in Hong psychiatric disturbance. Positive CT Kong scan with caudate atrophy considered to be ‘supportive’ of an HD diagnosis Chen 2010 Taiwan Outpatient and inpatient claims from Search of National Health Insurance the National Health Insurance Research Database for ICD-9 code Research Database 333.4 Australasia McCusker 2000 NSW, Records of the NSW HD Service. Definite: chorea or ataxia with a Australia Records of the major general and positive family history or expanded chronic psychiatric hospitals in NSW. CAG repeat Questionnaires to adult and paediatric neurologists, psychiatrists, genetic counsellors and clinical geneticists Europe Palo 1987 Finland Systematic search of all university, Not stated central, general and central psychiatric hospitals Govoni 1988 Ferrara, Italy Records of the neurology clinics of Combination of a positive family Ferrera and Bologna, civil records, history, choreiform movements, mental records of the psychiatric institutions, deterioration records of public and private geriatric nursing homes Ramos-Arroyo 2005 Navara and Referrals to the Medical Genetics Definite=typical clinical features plus Basque, Spain Laboratory of the Hospital Virgen del <36 CAG repeats plus positive family Camino, Pamplona, Spain, for history diagnostic testing for HD between Suspect=without positive family history 1993 and 2002. Also searched for additional patients from the Basque country who might have been referred to other HD diagnostic genetic centres in Spain. In addition, patients who underwent presymptomatic testing and became symptomatic within the study period were also included Mercy 2008 Cambridge Attendees/referrals to Addenbrooks’ UHDRS >5 UK Hospital memory/early dementia clinic Panas 2011 Greece Records of the Laboratory of Neurological examination including the Neurogenetics, Athens (the only UHDRS plus CAG repeat length in a neurogenetics lab in Greece) subset of patients Sackley 2011 UK Using THIN primary care research Based on recorded diagnosis database the authors identified Read codes for HD Sveinsson 2012 Iceland Medical records and hospital Hyperkinetic movement disorder plus discharge diagnoses of all hospitals psychiatric symptoms plus progressive including records of neurological, cognitive decline plus a positive family psychiatric and genetic departments. history or positive DNA analysis Information from practising neurologists and selected GPs. Information from family members Continued 6 Wexler NS, et al. BMJ Open 2016;6:e009070. doi:10.1136/bmjopen-2015-009070 Open Access Table 4 Continued Study ID Location Source of cases Diagnostic criteria Douglas 2013 UK Primary care National Health Service As recorded in patients’ electronic electronic health records health records (Read codes F134.00 and Eu2200) Current study UK Primary care National Health Service As recorded in patients’ electronic electronic health records health records (Read codes F134.00 and Eu2200) North America Kokman 1994 Minnesota, Scrutiny of records of hospitals, Definite HD=documented record of USA nursing homes, private practitioners, progressive choreiform movement state psychiatric hospital disorder; evidence of autosomal dominant inheritance; progressive cognitive, behavioural, and/or emotional dysfunction. Probable HD=2 out of 3 of the above criteria Almqvist 2001 British Patients referred to Medical Genetics Patients with signs and symptoms Columbia, Laboratory/HD clinic compatible with HD and with CAG Canada repeat lengths >36 HD, Huntington’s disease; GP, general practitioner; ICD, International Classification of Diseases; NSW, New South Wales; THIN, The Health Improvement Network; UHDRS, United Huntington’s Disease Rating Scale. incidence of HD is broadly consistent with the hetero- in different populations, may help to develop new thera- geneity of estimates of the prevalence of the condition. peutic strategies. Lower prevalence rates of HD have been noted in studies carried out in Asia compared with those among Author affiliations Department of Neurology and Psychiatry, Columbia University, New York, populations predominantly of European decent. The New York, USA estimates of incidence among Finish and Icelandic Hereditary Disease Foundation, New York, New York, USA peoples as well as Italians from the Ferrara region of 3 Department of Medical Statistics, London School of Hygiene and Tropical Italy are also compatible with the low prevalence rates in Medicine, London, UK these populations. The very low incidence of juvenile Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK HD, in the UK (0.70, 95% CI 0.36 to 1.22 per million Department of Neurodegenerative Diseases, Institute of Neurology, University person-years), is also consistent with its low prevalence College London, London, UK (6.77, 95%CI 5.6 to 8.12 per million) compared with the most recent (2010) estimate of the prevalence of adult Contributors All the authors contributed to the design of the study. Data extraction from CPRD was undertaken by LC, ID, SJE and LS. Data analyses HD (123, 95% CI 112 to 135 per million). were performed by LC, NSW and MDR. Statistical analyses were performed by Adefinitive molecular genetic test for the HD muta- LC, SJE and MDR. The systematic review was undertaken by ARW and MDR. tion has been available since the early 1990s in most All authors contributed to, and approved, the submitted manuscript. developed countries. Differences in the rates of genetic Funding The authors gratefully acknowledge support for this study from the testing might provide some explanation for the differ- Hereditary Disease Foundation, the Wellcome Trust and the Medical Research ences in the heterogeneity of estimates of incidence in Council. the populations studied. This explanation also seems Competing interests None declared. unlikely. For example, the overall incidence of HD in Ethics approval The study was approved from the CPRD’s Independent Taiwan, during the past decade, has remained consist- Scientific Advisory Committee and from the London School of Hygiene and ently lower than estimates from the UK over similar time Tropical Medicine’s Research Ethics Committee. periods. Provenance and peer review Not commissioned; externally peer reviewed. The present study suggests that, over the past two decades, the incidence of HD in the UK has remained Data sharing statement No additional data are available. constant despite a doubling of the prevalence of HD Open Access This is an Open Access article distributed in accordance with during this same time period. We also demonstrate that the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for there is significant heterogeneity in the estimates of the commercial use, provided the original work is properly cited. See: http:// incidence of HD carried out in other populations world- creativecommons.org/licenses/by/4.0/ wide. Particularly low estimates of incidence in Eastern Asia, as well as parts of Europe, suggests that modifiers of the expression of the disease may play an important REFERENCES role in determining the propensity of populations to be 1. Novak MJ, Tabrizi SJ. Huntington’s disease. BMJ 2010;341:34–40. vulnerable to expansions of the HD allele. Better 2. Wexler NS. Huntington’s disease: advocacy driving science. Annu understanding of the potential modifiers of expression, Rev Med 2012;63:1–22. Wexler NS, et al. BMJ Open 2016;6:e009070. doi:10.1136/bmjopen-2015-009070 7 Open Access 3. 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Journal

BMJ OpenBritish Medical Journal

Published: Feb 23, 2016

Keywords: EPIDEMIOLOGYGENETICS

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