Validation of self-reported help-seeking, and measurement of the patient interval, for cancer symptoms: an observational study to inform methodological challenges in symptomatic presentation research.

BACKGROUND: To improve earlier presentation with potential symptoms of cancer, accurate data are needed on how people respond to these symptoms. It is currently unclear how self-reported medical help-seeking for symptoms associated with cancer by people from the community correspond to what is recorded in their general practice records, or how well the patient interval (time from symptom onset to first presentation to a health-professional) can be estimated from patient records. METHOD: Data from two studies that reviewed general practice electronic records of residents in Scotland, (i) the 'Useful Study': respondents to a general population survey who reported experiencing symptoms potentially associated with one of four common cancers (breast, colorectal, lung and upper gastro-intestinal) and (ii) the 'Detect Cancer Early' programme: cancer patients with one of the same four cancers. Survey respondents' self-reported help-seeking (yes/no) was corroborated; Cohen's Kappa assessed level of agreement. Combined data on the patient interval were evaluated using descriptive analysis. RESULTS: 'Useful Study' respondents' self-report of help-seeking showed exact correspondence with general practice electronic records in 72% of cases (n = 136, kappa 0.453, moderate agreement). Between both studies, 1269 patient records from 35 general practices were reviewed. The patient interval could not be determined in 44% (n = 809) of symptoms presented by these individuals. CONCLUSIONS: Patient self-report of help-seeking for symptoms potentially associated with cancer offer a reasonably accurate method to research responses to these symptoms. Incomplete patient interval data suggest routine general practice records are unreliable for measuring this important part of the patient's symptom journey.

Why do patients discontinue antidepressant therapy early? A qualitative study.

BACKGROUND: Current guidelines for antidepressant prescribing are that treatment should be continued following the resolution of symptoms: six months after a first episode and for at least two years for those with previous episodes. Despite this, sub-optimal treatment duration still predominates. Patients have negative and positive views on antidepressants, which change throughout their treatment journey. OBJECTIVES: To explore views and experiences of patients recently initiated on antidepressants (within six months), and to consider the influences on early discontinuation. METHODS: A qualitative interview study was used in four general practices in the North East of Scotland. A purposive sample of primary care patients, newly initiated on antidepressants, was interviewed to explore views and experiences with antidepressant therapy. Interviews were audio-recorded and transcribed verbatim. Thematic analysis was conducted using a consensus coding frame developed by two researchers. RESULTS: Twenty-nine patients participated. Three main factors influencing discontinuation were identified: ownership, knowledge and support. The treatment journey was characterized by four important time points where health care intervention may be helpful. CONCLUSION: Health care professionals would benefit from exploring patient knowledge and views on depression and antidepressants at an early stage in treatment. Patients would welcome active involvement in treatment decision making, the provision of information and ongoing support.

Psychometric properties of the Quick Inventory of Depressive Symptomatology (QIDS-SR) in UK primary care.

It is widely believed that severity of depressive disorder should guide treatment selection and many guidelines emphasise this factor. The Quick Inventory of Depressive Symptomatology (QID-SR16) is a self-complete measure of depression severity which includes all DSM-IV criterion symptoms for major depressive disorder. The object of this study was to assess the psychometric properties of the QIDS-SR16 in a primary care sample. Adult primary care patients completed the QIDS-SR16 and were assessed by a psychiatrist (blind to QIDS-SR16) with the 17-item Hamilton Rating Scale for Depression (GRID-HAMD). Internal consistency, homogeneity and convergent and discriminant validity of the QIDS-SR16 were assessed. Severity cut-off scores for QIDS-SR16 were assessed for convergence with HRSD-17 cut-offs. Published methods for converting scores to HRSD-17 were also assessed. Two hundred and eighty-six patients participated: mean age = 49.5 (s.d. = 13.8), 68% female, mean HRSD-17 = 12.6 (s.d. = 7.6). The QIDS-SR16 exhibited acceptable internal consistency (Cronbach's alpha = 0.86), a robust factor structure indicating one underlying dimension and correlated highly with the HRSD-17 (r = 0.79) but differed significantly in how it categorised the severity of depression relative to the HRSD-17 (Wilcoxon Signed Rank Test p < 0.001). Using published methods to convert QIDS-SR16 scores to HRSD-17 scores did not result in alignment of severity categorisation. In conclusion, psychometric properties of the QIDS-SR16 were found to be strong in terms of internal consistency, factor structure and convergent and discriminant validity. Using conventional scoring and conversion methods the scale was found not to concur with the HRSD-17 in categorising the severity of depressive symptoms.

Recruiting children onto research studies by the Scottish Primary Care Research Network: a real team effort.

BACKGROUND: Recruiting for research studies is always a challenge, particularly in paediatric studies. Here we report on experiences recruiting children to five studies through primary care. METHODS: The Scottish Primary Care Research Network (SPCRN) has approval to identify for research studies eligible participants on primary care practice lists. The number of potential participants and the proportion recruited onto five paediatric studies are provided along with factors involved in recruiting practices and patients. RESULTS: A total of 4910 individuals were recruited, of whom 367 (7%) participated. Recruitment of practices varied between 7 and 44% for different studies. There was evidence that practices who had participated in previous studies were more likely to participate again. Patient participation was positively related to affluence and there was evidence that adults were more likely to participate than children. DISCUSSION: Despite the pressing clinical workload in primary care, many general practices are still able to make accommodation for research activity. What is required is effective communication between colleagues in primary care, researchers, the SPCRN and patients. Given that the majority of medicine is practiced in primary care, there is a desire for evidence-based medicine to be generated from primary care and the SPCRN and other networks can help to provide this.

Measuring depression severity in general practice: discriminatory performance of the PHQ-9, HADS-D, and BDI-II.

BACKGROUND: The UK Quality and Outcomes Framework (QOF) rewards practices for measuring symptom severity in patients with depression, but the endorsed scales have not been comprehensively validated for this purpose. AIM: To assess the discriminatory performance of the QOF depression severity measures. DESIGN AND SETTING: Psychometric assessment in nine Scottish general practices. METHOD: Adult primary care patients diagnosed with depression were invited to participate. The HADS-D, PHQ-9, and BDI-II were assessed against the HRSD-17 interview. Discriminatory performance was determined relative to the HRSD-17 cut-offs for symptoms of at least moderate severity, as per criteria set by the American Psychiatric Association (APA) and NICE. Receiver operating characteristic curves were plotted and area under the curve (AUC), sensitivity, specificity, and likelihood ratios (LRs) calculated. RESULTS: A total of 267 were recruited per protocol, mean age = 49.8 years (standard deviation [SD] = 14.1), 70% female, mean HRSD-17=12.6 (SD = 7.62, range = 0-34). For APA criteria, AUCs were: HADS-D = 0.84; PHQ-9 = 0.90; and BDI-II = 0.86. Optimal sensitivity and specificity were reached where HADS-D ≥9 (74%, 76%); PHQ-9 ≥12 (77%, 79%), and BDI-II ≥23 (74%, 75%). For NICE criteria: HADS-D AUC = 0.89; PHQ-9 AUC = 0.93; and BDI-II AUC = 0.90. Optimal sensitivity and specificity were reached where HADS-D ≥10 (82%, 75%), PHQ-9 ≥15 (89%, 83%), and BDI-II ≥28 (83%, 80%). LRs did not provide evidence of sufficient accuracy for clinical use. CONCLUSION: As selecting treatment according to depression severity is informed by an evidence base derived from trials using HRSD-17, and none of the measures tested aligned adequately with that tool, they are inappropriate for use.

Is there evidence for aetiologically distinct subgroups of idiopathic congenital talipes equinovarus? A case-only study and pedigree analysis.

BACKGROUND: Idiopathic congenital talipes equinovarus (CTEV) is a common developmental foot disorder, the aetiology of which remains largely unknown. Some aspects of the epidemiology suggest the possibility of aetiologically distinct subgroups. Previous studies consider CTEV as a homogenous entity which may conceal risk factors in particular subgroups. We investigate evidence for aetiologically distinct subgroups of CTEV. METHODS: Parents of 785 probands completed a postal questionnaire. Family pedigrees were compiled by telephone. Case-only analysis was used to investigate interactions between risk factors and sex of the proband, CTEV laterality and CTEV family history. RESULTS: The male:female ratio was 2.3:1, 58% of probands were affected bilaterally and 11% had a first-second degree family history. There were modest interactions between family history and twin births (multivariate case - only odds ratio [ORca] = 3.87, 95%CI 1.19-12.62) and family history and maternal use of folic acid supplements in early pregnancy (ORca = 0.62, 95%CI 0.38-1.01); and between sex of the proband and maternal alcohol consumption during pregnancy (female, positive history and alcohol consumed: ORca = 0.33, 95%CI 0.12-0.89). Previous reports of an interaction between maternal smoking and family history were not confirmed. Relatives of female probands were affected more often than relatives of male probands. CONCLUSIONS: These results provide tentative evidence for aetiologically distinct CTEV subgroups. They support the 'Carter effect', suggesting CTEV develops though a multifactorial threshold model with females requiring a higher risk factor 'load', and suggest areas where future aetiological investigation might focus. Large multi-centre studies are needed to further advance understanding of this common condition.

Analysing the SF-36 in population-based research. A comparison of methods of statistical approaches using chronic pain as an example.

BACKGROUND: The Medical Outcomes Study 36 Item Short-Form (SF-36) questionnaire is one of the most widely used measures of health related quality of life in medical research, including studies on pain-related conditions. Although scores in each of its eight domains rarely conform to a normal distribution, it is most widely analysed using simple parametric statistical techniques. Some have suggested a need for more complex or non-parametric analytical approaches, and this quandary faces researchers recurrently when using the SF-36. In this study of chronic pain, we compared results arising from the SF-36 between three study sub-samples, using conventional parametric, non-parametric, bootstrapping and log transforming methods. METHODS: Respondents to a postal survey conducted in Aberdeen, Leeds and London (n = 3002, response rate 52%) were categorized in three groups according to previously validated questionnaires: those with chronic pain of predominantly neuropathic origin (POPNO, n = 241), those with chronic pain (non-POPNO, n = 1179), and those with no chronic pain (n = 1537). SF-36 scores were compared between these groups, using: ANOVA and t-tests; Kruskall-Wallis and Mann-Whitney U-tests; bootstrapping methods; and log transformation with ANOVA. RESULTS: There were highly significant differences between the three groups, with lower scores in all SF-36 domains found those with chronic pain (P < 0.001). Those with chronic POPNO had lower scores in all domains than those with chronic pain (non-POPNO) (P < 0.001). These results were the same after applying each statistical method. CONCLUSIONS: In this study, the choice of statistical approach had no influence on the results. We conclude that the conventional approach, using straightforward parametric tests, is both simplest and the best for allowing comparison with other studies. We are likely to adopt this in future studies.

Variation in WNT7A is unlikely to be a cause of familial congenital talipes equinovarus.

BACKGROUND: Genetic factors make an important contribution to the aetiology of congenital talipes equinovarus (CTEV), the most common developmental disorder of the lower limb. WNT7A was suggested as a candidate gene for CTEV on the basis of a genome-wide scan for linkage in a large multi-case family. WNT7A is a plausible candidate gene for CTEV as it provides a signal for pattern formation during limb development, and mutation in WNT7A has been reported in a number of limb malformation syndromes. METHODS: We investigated the role of WNT7A using a family-based linkage approach in our large series of European multi-case CTEV families. Three microsatellite markers were used, of which one (D3S2385) is intragenic, and the other two (D3S2403, D3S1252) are 700 kb 5' to the start and 20 kb from the 3' end of the gene, respectively. Ninety-one CTEV families, comprising 476 individuals of whom 211 were affected, were genotyped. LOD scores using recessive and incomplete-dominant inheritance models, and non-parametric linkage scores, excluded linkage. RESULTS: No significant evidence for linkage was observed using either parametric or non-parametric models. LOD scores for the parametric models remained strongly negative in the regions between the markers, and in the 0.5 cM intervals outside the marker map. No significant lod scores were obtained when the data were analysed allowing for heterogeneity. CONCLUSION: Our evidence suggests that the WNT7A gene is unlikely to be a major contributor to the aetiology of familial CTEV.

Fetal anticonvulsant syndromes and polymorphisms in MTHFR, MTR, and MTRR.

The malformations found in fetal anticonvulsant syndromes (FACS) are associated with folic acid deficiency and methylene-tetrahydrofolate reductase (MTHFR) polymorphisms in the general population. To investigate a possible association between FACS and MTHFR genotype, we recruited 200 mothers who had taken anti-epileptic drugs in pregnancy, and delivered at Aberdeen Maternity Hospital over a 26-year period. Clinical findings in the mothers and their 337 children were documented. A clinical algorithm was devised to diagnose FACS objectively. Case-parent triads were genotyped for polymorphisms in MTHFR, serine hydroxymethyl transferase (SHMT1), methionine synthase (MTR), and methionine synthase reductase (MTRR), and analyzed by log-linear regression. No effect of the child's genotype on congenital malformation, neurodevelopmental disorder or FACS was detected using this method. The risk of having a child with congenital malformation or FACS was three to four times higher for mothers who were MTHFR 677TT homozygotes compared with MTHFR 677CC homozygotes. MTR 2756A > G and MTRR 66A > G genotype frequencies in children with FACS and neurodevelopmental disorder were different from those in healthy blood donor controls.

The C677T polymorphism in the methylenetetrahydrofolate reductase gene (MTHFR), maternal use of folic acid supplements, and risk of isolated clubfoot: A case-parent-triad analysis.

Worldwide, 1-4 per 1,000 births are affected by clubfoot. Clubfoot etiology is unclear, but both genetic and environmental factors are thought to be involved. Low folate status in pregnant women has been implicated in several congenital malformations, and folate metabolism may be affected by polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR). Using a case-parent-triad design, the authors investigated whether the MTHFR C677T polymorphism, and maternal periconceptional folic acid supplement use, influenced risk of isolated clubfoot. Three hundred seventy-five United Kingdom case-parent triads were recruited in 1998-1999. Among the children, there was a significant trend of decreasing clubfoot risk with increasing number of T alleles: relative risk for CT vs. CC = 0.75, 95% confidence interval: 0.57, 0.97; relative risk for TT vs. CC = 0.57, 95% confidence interval: 0.35, 0.91; p trend = 0.006. This association was not modified by maternal folic acid use. Maternal MTHFR genotype did not influence clubfoot risk for the offspring overall, although a possible interaction with folic acid use was found. This is the first known report of a specific genetic polymorphism associated with clubfoot. The direction of the association is intriguing and suggests that DNA synthesis may be relevant in clubfoot development. However, clubfoot mechanisms are poorly understood, and the folate metabolism pathway is complex. Further research is needed to elucidate these relations.

Maternal medication use and the risk of brain tumors in the offspring: the SEARCH international case-control study.

N-nitroso compounds (NOC) have been associated with carcinogenesis in a wide range of species, including humans. There is strong experimental data showing that nitrosamides (R(1)NNO.COR(2)), a type of NOC, are potent neuro-carcinogens when administered transplacentally. Some medications are a concentrated source of amides or amines, which in the presence of nitrites under normal acidic conditions of the stomach can form NOC. Therefore, these compounds, when ingested by women during pregnancy, may be important risk factors for tumors of the central nervous system in the offspring. The aim of the present study was to test the association between maternal use of medications that contain nitrosatable amines or amides and risk of primary childhood brain tumors (CBT). A case-control study was conducted, which included 1,218 cases and 2,223 population controls, recruited from 9 centers across North America, Europe and Australia. Analysis was conducted for all participants combined, by tumor type (astroglial, primitive neuroectodermal tumors and other glioma), and by age at diagnosis (< or =5 years; >5 years). There were no significant associations between maternal intake of medication containing nitrosatable amines or amides and CBT, for all participants combined and after stratification by age at diagnosis and histological subtype. This is the largest case-control study of CBT and maternal medications to date. Our data provide little support for an association between maternal use of medications that may form NOC and subsequent development of CBT in the offspring.

Tobacco smoking and oral clefts: a meta-analysis.

OBJECTIVE: To examine the association between maternal smoking and non-syndromic orofacial clefts in infants. METHODS: A meta-analysis of the association between maternal smoking during pregnancy was carried out using data from 24 case-control and cohort studies. FINDINGS: Consistent, moderate and statistically significant associations were found between maternal smoking and cleft lip, with or without cleft palate (relative risk 1.34, 95% confidence interval 1.25-1.44) and between maternal smoking and cleft palate (relative risk 1.22, 95% confidence interval 1.10-1.35). There was evidence of a modest dose-response effect for cleft lip with or without cleft palate. CONCLUSION: The evidence of an association between maternal tobacco smoking and orofacial clefts is strong enough to justify its use in anti-smoking campaigns.