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1.  Lessons from Mackenzie that still resonate 
PMCID: PMC3582972  PMID: 23561780
2.  What's in a name? 
PMCID: PMC2034166  PMID: 17263923
3.  Genetic epidemiology and primary care 
Large-scale, population-based studies of genetic epidemiology are under way or planned in several countries, including the UK. The results will have many implications for GPs and their patients. Primary care has much to contribute to this research, and basing genetic epidemiology studies in primary care will confer several advantages. These include enhanced public engagement, building on the personal relationships and trust that are at the core of primary care practice; methodological factors that will strengthen study design; and the potential of linkage of multiple datasets and between networks of research practices. Essential development work with primary care professionals and the public is, however, required for this to happen, and, if undertaken, this work will have the additional important benefit of increasing the uptake of new knowledge into general practice.
PMCID: PMC1828265  PMID: 16536962
epidemiology; genetics; primary care; public engagement
4.  Substance misuse of gabapentin 
PMCID: PMC3404313  PMID: 22867659
5.  Neuropathic pain in the community: More under-treated than refractory? 
Pain  2013;154(5):690-699.
There is a significant proportion of chronic pain that is persistent and neuropathic, appears undertreated or untreated, and is associated with poor health and quality of life.
Best current estimates of neuropathic pain prevalence come from studies using screening tools detecting pain with probable neuropathic features; the proportion experiencing significant, long-term neuropathic pain, and the proportion not responding to standard treatment are unknown. These “refractory” cases are the most clinically important to detect, being the most severe, requiring specialist treatment. The aim of this study was to estimate the proportion of neuropathic pain in the population that is “refractory,” and to quantify associated clinical and demographic features. We posted self-administered questionnaires to 10,000 adult patients randomly selected from 10 general practitioner practices in 5 UK locations. The questionnaire contained chronic pain identification and severity questions, cause of pain, SF-12, EQ-5D, S-LANSS (Self-administered Leeds Assessment of Neuropathic Signs and Symptoms), PSEQ (Pain Self-Efficacy Questionnaire), use of neuropathic pain medications, and health care utilisation. These data were combined to determine the presence and characteristics of “refractory” neuropathic pain according to the defining features identified by a Delphi survey of international experts. Graded categories of chronic pain with and without neuropathic characteristics were generated, incorporating the refractory criteria. Completed questionnaires were returned by 4451 individuals (response rate 47%); 399 had “chronic pain with neuropathic characteristics” (S-LANSS positive, 8.9% of the study sample); 215 (53.9%) also reported a positive relevant history (“Possible neuropathic pain”); and 98 (4.5% of all Chronic Pain) also reported an “adequate” trial of at least one neuropathic pain drug (“Treated possible neuropathic pain”). The most refractory cases were associated with dramatically poorer physical and mental health, lower pain self-efficacy, higher pain intensity and pain-related disability, and greater health care service use.
PMCID: PMC3630326  PMID: 23485369
Neuropathic pain; Chronic pain; Epidemiology; S-LANSS; Refractory
6.  Genetic variation in Hyperpolarization-activated cyclic nucleotide-gated channels and its relationship with neuroticism, cognition and risk of depression 
Frontiers in Genetics  2012;3:116.
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are encoded by four genes (HCN1–4) and, through activation by cyclic AMP (cAMP), represent a point of convergence for several psychosis risk genes. On the basis of positive preliminary data, we sought to test whether genetic variation in HCN1–4 conferred risk of depression or cognitive impairment in the Generation Scotland: Scottish Family Health Study. HCN1, HCN2, HCN3, and HCN4 were genotyped for 43 haplotype-tagging SNPs and tested for association with DSM-IV depression, neuroticism, and a battery of cognitive tests assessing cognitive ability, memory, verbal fluency, and psychomotor performance. No association was found between any HCN channel gene SNP and risk of depression, neuroticism, or on any cognitive measure. The current study does not support a genetic role for HCN channels in conferring risk of depression or cognitive impairment in individuals from the Scottish population.
PMCID: PMC3387669  PMID: 22783272
stress; depression; HCN channel; genetics; association; cognition; neuroticism
7.  Towards a definition of refractory neuropathic pain for epidemiological research. An international Delphi survey of experts 
BMC Neurology  2012;12:29.
Best current estimates of neuropathic pain (NeuP) prevalence come from studies using various screening detecting pain with probable neuropathic features; the proportion experiencing significant, long-term NeuP, and the proportion not responding to standard treatment are unknown. These “refractory” cases are the most clinically important to detect, being the most severe, requiring specialist treatment.
We report an international Delphi survey of experts in NeuP, aiming for consensus on the features required to define, for epidemiological research: (1) neuropathic pain; and (2) when NeuP is “refractory”. A web-based questionnaire was developed and data collected from three rounds of questionnaires from nineteen experts.
There was good consensus on essential inclusion of six items to identify NeuP (“prickling, tingling, pins & needles”, “pain evoked by light touch”, “electric shocks or shooting pain”, “hot or burning” pain, “brush allodynia on self-examination”, and “relevant history”) and on some items that were non-essential. Consensus was also reached on components of a “refractory NeuP” definition: minimum duration (one year); number of trials of drugs of known effectiveness (four); adequate duration of these trials (three months / maximum tolerated); outcomes of treatment (pain severity, quality of life). Further work needs to validate these proposed criteria in general population research.
This paper presents an international consensus on measuring the epidemiology of refractory neuropathic pain. This will be valuable in reaching an agreed estimate of the prevalence of neuropathic pain, and the first estimate of refractory neuropathic pain prevalence.
PMCID: PMC3476440  PMID: 22640002
Neuropathic pain; Refractory; Epidemiology; Delphi method; Web-based questionnaire
8.  Commentary: This pain is killing me 
PMCID: PMC2828858  PMID: 20202353
10.  Symptom experience and subsequent mortality: results from the West of Scotland Twenty-07 study 
Associations between symptom experience and mortality have rarely been investigated. One study has suggested that the number of symptoms people experience may be an important predictor of mortality. This novel and potentially important finding may have important implications but needs to be tested in other cohorts.
858 people aged around 58 years were interviewed by nurses in 1990/1 as part of the West of Scotland Twenty-07 Study. They were asked about the presence of symptoms in the last month from a checklist of 33 symptoms. Measures of morbidity included symptom type (respiratory, musculoskeletal, gastrointestinal, mental health, neurological, systemic) and symptom summary measures looking at the number and impact of symptoms (total number; number participants tended to have; number participants did not tend to have; number which restricted usual activities; number which led to GP consultation). Hazard ratios for thirteen-year all-cause mortality were calculated for symptom types, symptom summary measures, and self-assessed health with and without adjustment.
On unadjusted analysis, and after adjusting for gender, socio-economic status and smoking, mortality was elevated in individuals reporting respiratory, systemic and mental health symptoms. After additional adjustment for chronic conditions and self-assessed health, only the association between mental health symptoms and mortality remained significant. On unadjusted analysis, and after adjusting for gender, socio-economic status and smoking, mortality was elevated in individuals with many (≥ 6) symptoms in four of the symptom summary measures examined. These relationships were no longer significant after additional adjustment for chronic conditions and self-assessed health. A clear trend of increasing mortality as self-assessed health became poorer was observed. This pattern remained statistically significant after adjustment for gender, socio-economic status, smoking, chronic conditions and the total number of symptoms experienced.
Symptoms often thought of as minor may have important consequences later in life especially for those reporting mental health-related symptoms or those experiencing many symptoms. In this study however, self-assessed health appeared to be a better predictor of mortality than the type or number of symptoms experienced, even when the tendency to have and impact of the symptoms were taken into account.
PMCID: PMC1702541  PMID: 17156478
11.  Generation Scotland: the Scottish Family Health Study; a new resource for researching genes and heritability 
BMC Medical Genetics  2006;7:74.
Generation Scotland: the Scottish Family Health Study aims to identify genetic variants accounting for variation in levels of quantitative traits underlying the major common complex diseases (such as cardiovascular disease, cognitive decline, mental illness) in Scotland.
Generation Scotland will recruit a family-based cohort of up to 50,000 individuals (comprising siblings and parent-offspring groups) across Scotland. It will be a six-year programme, beginning in Glasgow and Tayside in the first two years (Phase 1) before extending to other parts of Scotland in the remaining four years (Phase 2). In Phase 1, individuals aged between 35 and 55 years, living in the East and West of Scotland will be invited to participate, along with at least one (and preferably more) siblings and any other first degree relatives aged 18 or over. The total initial sample size will be 15,000 and it is planned that this will increase to 50,000 in Phase 2. All participants will be asked to contribute blood samples from which DNA will be extracted and stored for future investigation. The information from the DNA, along with answers to a life-style and medical history questionnaire, clinical and biochemical measurements taken at the time of donation, and subsequent health developments over the life course (traced through electronic health records) will be stored and used for research purposes. In addition, a detailed public consultation process will begin that will allow respondents' views to shape and develop the study. This is an important aspect to the research, and forms the continuation of a long-term parallel engagement process.
As well as gene identification, the family-based study design will allow measurement of the heritability and familial aggregation of relevant quantitative traits, and the study of how genetic effects may vary by parent-of-origin. Long-term potential outcomes of this research include the targeting of disease prevention and treatment, and the development of screening tools based on the new genetic information. This study approach is complementary to other population-based genetic epidemiology studies, such as UK Biobank, which are established primarily to characterise genes and genetic risk in the population.
PMCID: PMC1592477  PMID: 17014726
13.  Chronic pain and health status: how do those not using healthcare services fare? 
Relatively little is known about the clinical importance of symptoms not presented to healthcare services. Using data from a community survey we examined the health status among those with chronic pain who reported using or not using healthcare services. Individuals with chronic pain who had used healthcare services in the previous year had poorer health than symptomatic responders who had not used services, irrespective of the severity of chronic pain. The findings suggest that there is little point in trying to detect and treat individuals not currently presenting to healthcare services with their pain.
PMCID: PMC1324844  PMID: 15296563
health services; health services research; health status indicators; pain; signs and symptoms
15.  Pain and subsequent mortality and cancer among women in the Royal College of General Practitioners Oral Contraception Study. 
Recent research suggested associations between pain and subsequent all-cause and cancer-specific mortality. This study examined death and cancer development within six years of reporting pain, among women in the Royal College of General Practitioners Oral Contraception Study. We found no associations between 'any' or 'chronic' pain and subsequent all-cause mortality or cancer. We found a higher risk of death from respiratory disease among women reporting pain (adjusted odds ratio [AOR] = 2.5), a higher mortality among women reporting chronic chest pain (AOR = 1.75), and a higher risk of subsequent cancer among women reporting head or abdomen pain. Given the high prevalence of pain symptoms, these findings may be important, and warrant further research.
PMCID: PMC1314492  PMID: 12564277
16.  Assessing change in chronic pain severity: the chronic pain grade compared with retrospective perceptions. 
BACKGROUND: There is no standard method of measuring change in chronic pain severity. Clinical trials commonly use serial assessment scales, completed at two points in time, to estimate change in pain severity, while clinicians usually ask patients to make a retrospective assessment of change. How the two methods compare is not known. AIM: To assess different methods of measuring change in chronic pain severity, by comparing changes in scores on a serial measure of chronic pain severity using the Chronic Pain Grade (CPG) questionnaire and responders' retrospective perception of change in pain severity. DESIGN OF STUDY: Postal self-completion questionnaires. SETTING: The Grampian region of Scotland. METHOD: Postal questionnaires were sent in March and September 1998 to a random sample of 535 adults with chronic pain, drawn from responders to a postal survey of the region conducted in 1996. RESULTS: Corrected response rates of 87.5% and 90.7% were obtained. Over a six-month period poor levels of agreement were found, with responders' retrospective perceptions mirroring recorded changes in 41.8% of individuals (kappa = 0.081). A low partial correlation coefficient between the two measures (-0.209) was also found. Over a two-year period there were again poor levels of agreement, with responders' retrospective perceptions mirronng recorded changes in 35.2% of individuals (kappa = 0.071). A low partial correlation coefficient (-0.401) was again found. CONCLUSION: There was poor agreement and low correlation between two commonly used methods for assessing change in pain severity over time. This finding has important implications for both service practitioners and researchers.
PMCID: PMC1314266  PMID: 11942442
17.  Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region 
Annals of the rheumatic diseases  2012;72(3):427-436.
Chronic widespread pain (CWP) is a common disorder affecting ~10% of the general population and has an estimated heritability of 48-52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP.
We conducted a GWAS meta-analysis in 1,308 female CWP cases and 5,791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1,480 CWP cases and 7,989 controls (P<1×10−5). Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain.
The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of CCT5 and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (MAF=43%; OR=1.30, 95%CI=1.19-1.42, P=1.2×10−8). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95%CI=1.10-1.24, P=4.7×10−7) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95%CI=1.14-1.32, P=3.4×10−8, I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (P>7.7×10−4).
We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.
PMCID: PMC3691951  PMID: 22956598
Gene Polymorphism; Fibromyalgia/Pain Syndromes; Epidemiology
18.  Pedigree and genotyping quality analyses of over 10,000 DNA samples from the Generation Scotland: Scottish Family Health Study 
BMC Medical Genetics  2013;14:38.
Generation Scotland: Scottish Family Health Study (GS:SFHS) is a family-based biobank of 24,000 participants with rich phenotype and DNA available for genetic research. This paper describes the laboratory results from genotyping 32 single nucleotide polymorphisms (SNPs) on DNA from over 10,000 participants who attended GS:SFHS research clinics. The analysis described here was undertaken to test the quality of genetic information available to researchers. The success rate of each marker genotyped (call rate), minor allele frequency and adherence to Mendelian inheritance are presented. The few deviations in marker transmission in the 925 parent-child trios analysed were assessed as to whether they were likely to be miscalled genotypes, data or sample handling errors, or pedigree inaccuracies including non-paternity.
The first 10,450 GS:SFHS clinic participants who had spirometry and smoking data available and DNA extracted were selected. 32 SNPs were assayed, chosen as part of a replication experiment from a Genome-Wide Association Study meta-analysis of lung function.
In total 325,336 genotypes were returned. The overall project pass rate (32 SNPs on 10,450 samples) was 97.29%. A total of 925 parent-child trios were assessed for transmission of the SNP markers, with 16 trios indicating evidence of inconsistency in the recorded pedigrees.
The Generation Scotland: Scottish Family Health Study used well-validated study methods and can produce good quality genetic data, with a low error rate. The GS:SFHS DNA samples are of high quality and the family groups were recorded and processed with accuracy during collection of the cohort.
PMCID: PMC3614907  PMID: 23521772
Genetics; SNP Genotyping; Parent-child trios; Error rate; Non paternity; Generation Scotland; Biobank
19.  “I feel so stupid because I can’t give a proper answer…” How older adults describe chronic pain: a qualitative study 
BMC Geriatrics  2012;12:78.
Over 50% of older adults experience chronic pain. Poorly managed pain threatens independent functioning, limits social activities and detrimentally affects emotional wellbeing. Yet, chronic pain is not fully understood from older adults’ perspectives; subsequently, pain management in later life is not necessarily based on their priorities or needs. This paper reports a qualitative exploration of older adults’ accounts of living with chronic pain, focusing on how they describe pain, with a view to informing approaches to its assessment.
Cognitively intact men and women aged over sixty-five who lived in the community opted into the study through responding to advertisements in the media and via contacts with groups and organisations in North-East Scotland. Interviews were transcribed and thematically analysed using a framework approach.
Qualitative individual interviews and one group interview were undertaken with 23 older adults. Following analysis, the following main themes emerged: diversity in conceptualising pain using a simple numerical score; personalising the meaning of pain by way of stories, similes and metaphors; and, contextualising pain in relation to its impact on activities.
The importance of attending to individuals’ stories as a meaningful way of describing pain for older adults is highlighted, suggesting that a narrative approach, as recommended and researched in other areas of medicine, may usefully be applied in pain assessment for older adults. Along with the judicious use of numerical tools, this requires innovative methods to elicit verbal accounts, such as using similes and metaphors to help older adults describe and discuss their experience, and contextualising the effects of pain on activities that are important to them.
PMCID: PMC3544685  PMID: 23276327
Older adults; Ageing; Qualitative research; Stories; Metaphors; Chronic pain; Community
20.  Effect of Five Genetic Variants Associated with Lung Function on the Risk of Chronic Obstructive Lung Disease, and Their Joint Effects on Lung Function 
Rationale: Genomic loci are associated with FEV1 or the ratio of FEV1 to FVC in population samples, but their association with chronic obstructive pulmonary disease (COPD) has not yet been proven, nor have their combined effects on lung function and COPD been studied.
Objectives: To test association with COPD of variants at five loci (TNS1, GSTCD, HTR4, AGER, and THSD4) and to evaluate joint effects on lung function and COPD of these single-nucleotide polymorphisms (SNPs), and variants at the previously reported locus near HHIP.
Methods: By sampling from 12 population-based studies (n = 31,422), we obtained genotype data on 3,284 COPD case subjects and 17,538 control subjects for sentinel SNPs in TNS1, GSTCD, HTR4, AGER, and THSD4. In 24,648 individuals (including 2,890 COPD case subjects and 13,862 control subjects), we additionally obtained genotypes for rs12504628 near HHIP. Each allele associated with lung function decline at these six SNPs contributed to a risk score. We studied the association of the risk score to lung function and COPD.
Measurements and Main Results: Association with COPD was significant for three loci (TNS1, GSTCD, and HTR4) and the previously reported HHIP locus, and suggestive and directionally consistent for AGER and TSHD4. Compared with the baseline group (7 risk alleles), carrying 10–12 risk alleles was associated with a reduction in FEV1 (β = –72.21 ml, P = 3.90 × 10−4) and FEV1/FVC (β = –1.53%, P = 6.35 × 10−6), and with COPD (odds ratio = 1.63, P = 1.46 × 10−5).
Conclusions: Variants in TNS1, GSTCD, and HTR4 are associated with COPD. Our highest risk score category was associated with a 1.6-fold higher COPD risk than the population average score.
PMCID: PMC3398416  PMID: 21965014
FEV1; FVC; genome-wide association study; modeling risk

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