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College Research Ethics Committee
APPLICATION FOR CREC APPROVAL
Please type in the grey boxes, which will expand automatically to encompass your text. Use the mouse or the tab key (with picture of two arrows, normally above the CAPS LOCK key) to move between the boxes. Remember that the application and all accompanying documents will have to be printed out, authorised, and eighteen copies (one original and 17 double-sided photocopies) sent to the CREC office, Room 7.21 James Clerk Maxwell Building, Waterloo Campus, Kings College London, 57 Waterloo Road, London SE1 8WA.
1. TITLE OF STUDY (HYPERLINK "Guidelines, revised 180603.doc" \l "TITLE"guidance note 1)
Cardiovascular risk, nutrition and dementia incidence and dementia incidence in admixed populations undergoing rapid health transition Latin America and China
2. NATURE OF PROJECT (HYPERLINK "Guidelines, revised 180603.doc" \l "NATURE"guidance note 2)
Original research
3. INVESTIGATORS (HYPERLINK "Guidelines, revised 180603.doc" \l "INVESTIGATORS"guidance note 3)
3a. Principal Investigator
Name: Martin Prince
Post: Professor Department: Health Services Research Institute of Psychiatry
Qualifications: MD MSc MRCPsych
Please list your experience of Research on Human Participants:
I was the PI for the successful baseline dementia surveys in the 9 overseas centres included in this application (for an incidence phase)
I also have extensive experience over 15 years as PI for numerous epidemiological survey based projects in the UK and in many developing country settings
3b. Other investigators / collaborators (please note their employer if other than Kings College, London and the qualification being worked towards if the investigator is a student):
1.Prof Paul McKeigue, Genetics & Epidemiology Department - Conway Institute University College Dublin- Belfield Campus, Belfield, Dublin 4 Ireland
2. Dr. Robert Stewart, Institute of Psychiatry, Kings college London
3. Dr. Juan Llibre Rodrigues, Facultad de Medicina Finley-Albarran, Medical University of Havana,Cuba.
4. Dr. Daisy Acosta, Universidad Nacional Pedro Enrique Urena (UNPHU) venida John F Kennedy, Esquina Abraham Lincoln, Departamento de Medicina Interna, Seccin de geriatria, Santo Domingo, Dominican Republic
5. Dr. Aquiles Salas , Departamento de medicina , Hospital Universitario de caracas, Fcultad de medicina, Universidad Central de Venezuela, Caracas, Venezuela
6. Dr. Raul Arizaga, Behavioral and Cognitive Neurology Unit Neuraxis Institute Neurological Foundation, Buenos ires rgentina
7. Dr, Mariella Guerra Psychogeriatric Unit, National Institute of mental helath Honorio Delagado Hideyo Noguchi Avda. Jos Galvez Barrenechea N. 274. Dpto 401.
Corpac -SAN ISIDRO Lima Per
8. Dr. Ana Luisa Sosa, The cognitive and Behavior Unit, National Institute of Neurology and Neurosurgery of Mexico, v Insurgentes, 3877 Col. La fama. Cp 14269.
Delegacion Tlalpan. Mexico City Mexico.
9. Dr Yueqin Huang, Peking University Institute of Mental Health. No. 51 Hua Yuan Bei Road Haidian District Beijing, 100083 China
4. PREFERRED TIMETABLE (HYPERLINK "Guidelines, revised 180603.doc" \l "TIMETABLE"guidance note 4)
4a. Preferred start date: January 2007
4b. Projected date of projects completion: December 2010
5. SPONSOR / OTHER ORGANISATIONS INVOLVED AND FUNDING (HYPERLINK "Guidelines, revised 180603.doc" \l "SPONSOR"guidance note 5)
5a. KCL
If other: FORMTEXT
5 b . I f y o u r s t u d y i n v o l v e s a n o t h e r o r g a n i s a t i o n , p l e a s e p r o v i d e d e t a i l s . E v i d e n c e t h a t t h e r e l e v a n t a u t h o r i t y h a s g i v e n p e r m i s s i o n , i . e . a l e t t e r , i s l i k e l y t o b e n e c e s s a r y .
1 . F a c u l t a d d e M e d i c i n a F i n l e y - A l b a r r a n , M e d i c a l U n i v e r s i t y o f H a v a n a , C u b a.
2. Universidad Nacional Pedro Enrique Urena (UNPHU) Avenida John F Kennedy, Esquina Abraham Lincoln, Departamento de Medicina Interna, Seccin de Geriatria, Santo Domingo, Dominican Republic
3. Departamento de medicina , Hospital Universitario de caracas, Facultad de Medicina, Universidad Central de Venezuela, Caracas, Venezuela
4. Behavioral and Cognitive Neurology Unit Neuraxis Institute Neurological Foundation, Buenos ires rgentina
5. National Institute of mental health Honorio Delagado Hideyo Noguchi Avda. Jos Galvez Barrenechea N. 274. Dpto 401. Corpac -SAN ISIDRO Lima Per
6. The cognitive and Behavior Unit, National Institute of Neurology and Neurosurgery of Mexico, v Insurgentes, 3877 Col. La fama. Cp 14269.
Delegacion Tlalpan. Mexico City Mexico.
7. Peking University Institute of Mental Health. No. 51 Hua Yuan Bei Road Haidian District Beijing, 100083 China
Local ethical approval is currently being sought in all overseas centres
5c. If you are receiving funding for the study please provide details here.
The Wellcome Trust has awarded the Institute of Psychiatry 1,478019 for research assistance, expenses and equipment, for 54 months, for this study. Part of the funds will be transmitted to the 7 centres to pay research assistants salaries and other costs associated to the project.
6. OTHER REC APPROVAL HYPERLINK "Guidelines, revised 180603.doc" \l "LREC" (see introduction for guidance on when LREC approval is necessary)
6a. Has the proposed study been submitted to any other reviewing body? If so, please provide details.
No
7. PURPOSE OF THE STUDY (HYPERLINK "Guidelines, revised 180603.doc" \l "PURPOSE"guidance note 7)
Research question:
What are the genetic and environmental risk determinants for dementia in Latin American and Chinese populations undergoing rapid demographics ageing and health transition?
Are cardiovascular risk factors also risk factors for dementia/ AD in these settings, as in developed countries?
In the admixed populations, are those with greater degrees of African ancestry relatively protected from the disease?
Can research in admixed populations help us to understand ethnic differences in risk determinants for cardiovascular disease, dementia, and associations between the two?
Is micronutrient deficiency a risk factor for dementia in the relatively poor communities selected for our research programme?
Objectives:
main objectives
1. To create a publicly accessible data archive from the 10/66 Dementia Research Groups cross-sectional population-based surveys including over 17,000 older people from nine countries in Latin America, the Caribbean, India and China.
1.1 To use these data for comparative descriptive analyses of dementia prevalence, and its associated impact including
1.1.1 the economic costs of illness in each centre including indirect (informal care) costs, lost earnings and direct costs (health and social care and medication).
1.1.2 the relative independent contribution of dementia and other major non-communicable disorders to direct and indirect costs, disability, dependency and caregiver strain.
1.2 To model dementia prevalence, examining the effects of age, education, literacy and SES, and at population level of urban vs rural setting, historical levels of infant mortality, economic development, and industrialization.
2. To conduct a 2.5 to three year incidence phase follow-up of the baseline sample
The incidence phase will exploit the particularly rich baseline cross-sectional data in six Latin American countries (Cuba, the Dominican Republic, Venezuela, Mexico, Peru and Argentina) and in China, aiming:
2.1 To estimate the annual incidence rate of dementia and its subtypes, by age group, education and centre.
2.2 To investigate risk factors for incident dementia and AD, testing the following specific hypotheses:
2.2.1 cardiovascular risk factors (diabetes, hypertension, large waist circumference, high waist hip ratio, hypercholesterolaemia, hypertriglyceridaemia, metabolic syndrome and smoking) and stroke increase the risk for incident dementia and AD, after controlling for confounding effects. Associations will be quantified as relative risks and population attributable fractions.
2.2.2 micronutrient deficiencies (vitamin B12 and folate), and anaemia increase the risk for incident dementia and AD, and mediate any effect on these outcomes of overall nutritional deficiency.
2.2.3 sub-clinical hypothyroidism is associated with increased risk of dementia and AD.
2.2.3 incident dementia and AD are inversely associated with the proportion of the genome that is of African ancestry, and the association between APOE e4 genotype and incident dementia and AD is modified by admixture proportions weaker in those with least African ancestry.
3. To confirm the predictive validity of the survey dementia diagnoses (DSM IV and the 10/66 dementia algorithm and Mild Cognitive Impairment (MCI) through three year follow-up of all dementia and MCI cases. This will include a longitudinal study of evolving care arrangements and caregiver strain.**
** This element of the programme is described in more detail in a separate but linked application for a Masters level fellowship for Mr Jothish Waran, working in the Chennai centre in India. We will not present further details here.
secondary objectives
1. Mortality
1.1 To estimate annual all-cause and cause-specific mortality in each incidence centre and the independent effects upon all-cause and cardiovascular mortality of education, socio-economic status, cardiovascular risk factors (CVRF), prevalent cardiovascular disease (CVD), dementia, cognitive impairment, and depression
2. Stroke
2.1 To estimate, in the same centres the annual attack rates for stroke.
2.2 To compare the risk factor profile for incident stroke (relative risks and population attributable risk fractions) between centres, and within centres between men and women and better and less well educated participants.
3. Depression
3.1 to study the social aetiology of late-life depression cross-sectionally in all nine centres, and prospectively in the incidence centres including the effects of relative and absolute poverty, ill health and disability, nutritional status, social support, life events, marital circumstances and living arrangements.
Demographic ageing proceeds apace in all world regions. The proportion of older people increases as mortality falls and life expectancy increases. Latin America, China and India are experiencing unprecedentedly rapid demographic ageing.
In the accompanying health transition non-communicable diseases (NCD) assume a progressively greater significance in low and middle income countries (LMICs). NCDs are already the leading cause of death in all world regions apart from sub-Saharan Africa. This is partly because most of the worlds older people live in these regions - 60% now rising to 80% by 2050. However, changing patterns of risk exposure also contribute. Latin America exemplifies the third stage of health transition. As life expectancy improves, and high fat diets, cigarette smoking and sedentary lifestyles become more common, so CVDs have maximum public health salience. We recently estimated 24.2 million people living with dementia worldwide (based upon systematic review of prevalence data and expert consensus), with 4.6 million new cases annually (similar to the annual global incidence of non-fatal stroke). Most people with dementia live in LMICs; 60% in 2001 rising to 71% by 2040. Numbers will double every twenty years to over 80 millions by 2040. Increases to 2040 will be much sharper in developing (300%) than developed regions (100%). Growth in Latin America will exceed that of any other world region.
Well designed epidemiological research can generate awareness, inform policy, and encourage service development. However, such evidence is lacking in many world regions, and patchy in others, with few studies and widely varying estimates. There is a particular dearth of published epidemiological studies in Latin America with two descriptive studies only, from Brazil, and Colombia.
Prevalence is somewhat lower in developing countries than in the developed north, strikingly so in some studies. Mild dementia may be under-detected because of difficulties in establishing the criterion of social impairment. Differences in levels of exposure to environmental risk factors may also have contributed, with low levels of cardiovascular risk suggested as an explanation.
Other potential risk exposures will be more prevalent in LMICs, for example anaemia. Dietary deficiencies, particularly of micronutrients, are widespread and strongly linked to poverty. Deficiencies of folate and vitamin B12 are of particular interest given their consequences; anaemia, increased risk of stroke and IHD. Vitamin B12 deficiency is strikingly prevalent (> 40%) across Latin America. Folate deficiency is endemic in those living in poverty. Micronutrient deficiency is probably more prevalent in the elderly but there are few data on this age group.
High infant mortality may contribute to population differences in dementia frequency; constitutional and genetic factors that confer survival advantage in early years may protect against neurodegeneration or delay its clinical manifestations. It seems plausible that as patterns of morbidity and mortality converge with those of the developed west, then dementia prevalence will do likewise.
8. STUDY DESIGN, METHODOLOGY AND DATA ANALYSIS (HYPERLINK "Guidelines, revised 180603.doc" \l "DESIGN"guidance note 8)
FORMTEXT
S t u d y d e s i g n
A l l p a r t i c i p a n t s i n t h e c r o s s - s e c t i o n a l s u r v e y s i n C u b a , D o m i n i c a n R e p u b l i c , V e n e z u e l a a n d C h i n a w i l l b e r e c o n t a c t e d a n d r e s u r v e y e d t h r e e y e a r s a f t e r t h e i r b a s e l i n e a s s e s s m e n t . F o l l o w - u p a s s e s s m e n t s i n M e x i c o , A r g e n t i n a a n d P e r u w i l l be carried out 2.5 years after baseline, owing to the later start of the field work in these centres.
Response rates for the baseline surveys were very high (see Table 1). For the follow-up, which was pre-planned at baseline, we have collected the names, addresses and telephone numbers of three non co-resident local relatives, friends or neighbours who can be contacted to help trace the participant if they are not at their original address. The population in each of the settings where we are working is stable. Apart from a likely 6% per annum attrition from mortality, we anticipate a very high follow-up rate, in excess of that typically achieved in cohort studies in developed countries.
All methods, procedures and logistics are well established from the 10/66 baseline surveys. All assessments have been translated into the relevant local languages (Ibero-American Spanish and Mandarin). Trained, experienced research workers are available for the follow-up assessments. A standardized operating procedures manual covers every aspect of the training and field procedures. This is now being revised for the incidence phase. All data is double-entered into EpiData, with interactive range checks and skips. Data is extracted into SPSS, and all processing (cleaning, processing of derived variables and running of 10/66, DSMIV dementia and other diagnostic algorithms) is carried out using SPSS batch files. The end result is a cleaned, processed and labelled data set, that can be exported into other statistical programs (eg STATA) for further analysis. In the interests of transparency, all interviews, data entry files, algorithms, protocols, training materials and manuals can be downloaded from our intranet site
HYPERLINK "http://www.alz.co.uk/intranet/1066" http://www.alz.co.uk/intranet/1066
overall follow-up assessment strategy
There will be three groups of interest.
1) those who died between baseline and follow-up (information ascertained on follow-up visit)
2) those who were cases of DSMIV dementia or 10/66 dementia at baseline
3) all others
The second and third of these groups will receive the same assessment. The second group will have been at risk for stroke, and we will repeat dementia assessments to assess course and outcome, and to validate baseline diagnoses. Interviewers will be blinded to baseline diagnostic status.
1) those who have died in the interval between baseline and follow-up
We will complete a verbal autopsy interview with a co-resident, relative or other person well-placed to know the circumstances of death using methods developed and validated by the Million Deaths project for use in India ADDIN REFMGR.CITE Jha20051664Prospective Study of One Million Deaths in India: Rationale, Design, and Validation ResultsJournal1664Prospective Study of One Million Deaths in India: Rationale, Design, and Validation ResultsJha,P.Gajalakshmi,V.Gupta,P.C.Kumar,R.Mony,P.Dhingra,N.Peto,R.2005/12/20AdultAgeAlcoholbloodBlood PressureCase-controlCause of DeathChildclassificationDeathDeveloping CountriesGenderIndiamethodsMortalitynewProspective StudiesRiskRisk FactorsRisk TakingSmokingValidationNot in Filee18PLoS.Med.32PLoS.Med.1Gajalakshmi20041665Verbal autopsy of 80,000 adult deaths in Tamilnadu, South IndiaJournal1665Verbal autopsy of 80,000 adult deaths in Tamilnadu, South IndiaGajalakshmi,V.Peto,R.2004/10/15AdultAgeAge FactorsAgedAutopsyCause of DeathComparative StudyCoroners and Medical ExaminersDeathDeath CertificatesDeveloping CountriesdiagnosisDocumentationEducationepidemiologyFemaleHumansIndiaInservice TrainingInterviewsLanguagemethodsMiddle AgeMiddle AgedMortalityNeoplasmsQuestionnairesResearch Support,Non-U.S.Gov'tRuralRural PopulationSensitivity and Specificitystandardsstatistics & numerical datatreatmentUrbanUrban PopulationValidationNot in File47BMC.Public Health4BMC.Public Health1(1;2) to identify underlying cause according to ICD10 criteria. The interview takes 30-45 minutes using structured questions and an open-ended narrative, with a symptom list to assist attribution. Cause of death is allocated by the consensus judgement of two physicians. The approach is valid for use up to three years post-mortem. We will also attempt to ascertain whether the participant had an onset of dementia before death, using the standard 10/66 informant assessment (see Annex 1)
2) all others
The interviews for the incidence phase largely involve a repeat of the one phase dementia diagnostic protocol described in detail in Annex 1, with the aim of identifying incident dementia. We will also reassess risk exposures that may have changed over the three years since baseline, and review care arrangements, dependency and indices of caregiver strain. We include a two phase clinical protocol designed to identify incident stroke
Interviews will be carried out in participants own homes or in local polyclinics. Interviewers will work in pairs; one can interview the older participant, and the other the caregiver or co-resident.
Interviews and measures: This is a comprehensive one phase survey all participants receive the full assessment, lasting approximately 2-3 hours.
1) Outcome - The diagnosis of dementia.
Our previously published 10/66 dementia diagnosis algorithm ADDIN REFMGR.CITE Prince20031490Dementia diagnosis in developing countries: a cross-cultural validation studyJournal1490Dementia diagnosis in developing countries: a cross-cultural validation studyPrince,M.Acosta,D.Chiu,H.Scazufca,M.Varghese,M.2003DementiaDementia diagnosisCross-culturalValidationNot in File909917The Lancet361The Lancet1(3) requires
(i) A structured clinical mental state interview, the Geriatric Mental State, which applies a computer algorithm (AGECAT) ADDIN REFMGR.CITE Copeland1986459A computerised psychiatric diagnostic system and case nomenclature for elderly subjects: GMS and AGECATJournal459A computerised psychiatric diagnostic system and case nomenclature for elderly subjects: GMS and AGECATCopeland,J.R.M.Dewey,M.E.Griffith-Jones,H.M.1986elderlyNot in File8999Psychological Medicine16Psychological Medicine1(4), identifying organicity (prob. dementia), depression, anxiety and psychosis and,
(ii) A cognitive test battery comprising a) the Community Screening Instrument for Dementia (CSID) COGSCORE ADDIN REFMGR.CITE Hall1993661The development of a dementia screeing interview in two distinct languagesJournal661The development of a dementia screeing interview in two distinct languagesHall,K.S.Hendrie,H.H.Brittain,H.M.Norton,J.A.Rodgers,D.D.Prince,C.S.Pillay,N.Blue,A.W.Kaufert,J.N.Nath,A.Shelton,P.Postl,B.D.Osuntokun,B.O.1993goaDementiaInterviewsLanguageNot in File128International Journal of Methods in Psychiatric Research3International Journal of Methods in Psychiatric Research1(5) (incorporating the CERAD animal naming verbal fluency task), and b) the modified CERAD 10 word list learning task with delayed recall ADDIN REFMGR.CITE Ganguli M.19961242Cognitive test performance in a community-based non demented elderly sample in rural India: the Indo-US cross national dementia epidemiology studyJournal1242Cognitive test performance in a community-based non demented elderly sample in rural India: the Indo-US cross national dementia epidemiology studyGanguli M.,Chandra V.,Gilbey J.,1996elderlyRuralDementiaDementia epidemiologyNot in File507524International Psychogeriatrics8International Psychogeriatrics1(6) and
(iii) An informant interview the CSID RELSCORE ADDIN REFMGR.CITE Hall1993661The development of a dementia screeing interview in two distinct languagesJournal661The development of a dementia screeing interview in two distinct languagesHall,K.S.Hendrie,H.H.Brittain,H.M.Norton,J.A.Rodgers,D.D.Prince,C.S.Pillay,N.Blue,A.W.Kaufert,J.N.Nath,A.Shelton,P.Postl,B.D.Osuntokun,B.O.1993goaDementiaInterviewsLanguageNot in File128International Journal of Methods in Psychiatric Research3International Journal of Methods in Psychiatric Research1(5), for evidence of cognitive and functional decline
(iv) an extended informant interview, the History and Aetiology Schedule Dementia Diagnosis and Subtype (HAS-DDS), a modification of the earlier HAS ADDIN REFMGR.CITE Dewey20011595Diagnosis of dementia from the history and aetiology scheduleJournal1595Diagnosis of dementia from the history and aetiology scheduleDewey,M.E.Copeland,J.R.2001/9AetiologyDementiadiagnosisIncidencemethodsValidationNot in File912917International Journal of Geriatric Psychiatry169International Journal of Geriatric Psychiatry1(7), providing more detailed information on onset and course of a possible dementia syndrome
v) The NEUROEX, a brief fully structured neurological assessment with objectified quantifiable measures of lateralising signs, parkinsonism, ataxia, apraxia and primitive 'release' reflexes ADDIN REFMGR.CITE Broe19761038Neurological disorders in the elderly at homeJournal1038Neurological disorders in the elderly at homeBroe,G.A.Akhtar,A.J.Andrews,G.R.Caird,F.I.Gilmore,A.J.McLennan,W.J.1976elderlyAgedPrevalenceAgeDementiaAge FactorsCerebrovascular Disorders epidemiologyDementia epidemiologyMovement Disorders epidemiologyPeripheral Nervous System Diseases epidemiologyScotlandSex FactorsNot in File361366.J Neurol.Neurosurg.Psychiatry394.J Neurol.Neurosurg.Psychiatry1Broe19981259Impact of chronic systemic and neurological disorders on disability, depression and life satisfaction [published erratum appears in Int J Geriatr Psychiatry 1999 Jun;14(6):497-8]Journal1259Impact of chronic systemic and neurological disorders on disability, depression and life satisfaction [published erratum appears in Int J Geriatr Psychiatry 1999 Jun;14(6):497-8]Broe,G.A.Jorm,A.F.Creasey,H.Grayson,D.Edelbrock,D.Waite,L.M.Bennett,H.Cullen,J.S.Casey,B.1998=OctEducationDisabilitydepressionAgedVascularVascular diseaseDementiaassociationAgepredictNot in File667673International Journal of Geriatric Psychiatry1310International Journal of Geriatric Psychiatry1(8;9) .
Final dementia diagnoses is made in two ways.
1) 10/66 dementia defined as those scoring above a cutpoint of predicted probability of caseness derived from the logistic regression equation developed in the 10/66 international pilot study, using coefficients from the GMS, CSI-D and 10 word list learning tasks ADDIN REFMGR.CITE Prince20031490Dementia diagnosis in developing countries: a cross-cultural validation studyJournal1490Dementia diagnosis in developing countries: a cross-cultural validation studyPrince,M.Acosta,D.Chiu,H.Scazufca,M.Varghese,M.2003DementiaDementia diagnosisCross-culturalValidationNot in File909917The Lancet361The Lancet1(3).
2) DSM IV dementia by direct application of research diagnostic criteria for DSM IV and for the following dementia subtype diagnoses; NINCDS-ADRDA Alzheimers disease criteria, NINDS-AIREN vascular dementia criteria, and Lewy Body Dementia. The clinical assessment identifies other conditions relevant to the differential diagnosis of dementia and dementia sub-type: psychosis, depression, anxiety disorder, alcoholism, epilepsy, stroke and delirium. For the incidence phase we will modify the DSMIV algorithm to incorporate cognitive test and informant data from baseline into the direct determination of cognitive and functional decline.
ADDIN REFMGR.REFLIST Reference List for assessments
(1) Jha P, Gajalakshmi V, Gupta PC, Kumar R, Mony P, Dhingra N et al. Prospective Study of One Million Deaths in India: Rationale, Design, and Validation Results. PLoS Med 2005 December 20;3(2):e18.
(2) Gajalakshmi V, Peto R. Verbal autopsy of 80,000 adult deaths in Tamilnadu, South India. BMC Public Health 2004 October 15;4:47.
(3) Prince M, Acosta D, Chiu H, Scazufca M, Varghese M. Dementia diagnosis in developing countries: a cross-cultural validation study. The Lancet 2003;361:909-17.
(4) Copeland JRM, Dewey ME, Griffith-Jones HM. A computerised psychiatric diagnostic system and case nomenclature for elderly subjects: GMS and AGECAT. Psychological Medicine 1986;16:89-99.
(5) Hall KS, Hendrie HH, Brittain HM, Norton JA, Rodgers DD, Prince CS et al. The development of a dementia screeing interview in two distinct languages. International Journal of Methods in Psychiatric Research 1993;3:1-28.
(6) Ganguli M., Chandra V., Gilbey J. Cognitive test performance in a community-based non demented elderly sample in rural India: the Indo-US cross national dementia epidemiology study. International Psychogeriatrics 1996;8:507-24.
(7) Dewey ME, Copeland JR. Diagnosis of dementia from the history and aetiology schedule. International Journal of Geriatric Psychiatry 2001 September;16(9):912-7.
(8) Broe GA, Akhtar AJ, Andrews GR, Caird FI, Gilmore AJ, McLennan WJ. Neurological disorders in the elderly at home. J Neurol Neurosurg Psychiatry 1976;39(4):361-6.
(9) Broe GA, Jorm AF, Creasey H, Grayson D, Edelbrock D, Waite LM et al. Impact of chronic systemic and neurological disorders on disability, depression and life satisfaction [published erratum appears in Int J Geriatr Psychiatry 1999 Jun;14(6):497-8]. International Journal of Geriatric Psychiatry 1998;13(10):667-73.
(10) Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005 December 17;366(9503):2112-7.
Incident stroke
All those claiming (by participant or informant report) to have experienced a stroke in the interval between assessments, and all those with suggestive neurological signs (asymmetric long tract signs, dysphasia, marked gait disturbance) not apparent at baseline will be offered physician assessment including physical examination, clinical history, and examination of clinical notes and investigations where available (cold pursuit). We will then seek consensus diagnosis from two local independent experts. Stroke diagnosis (ARIC criteria) require
a) evidence of sudden or rapid onset of neurological symptoms
b) lasting for more than 24 hours or leading to death,
c) in the absence of evidence for a nonstroke cause (brain trauma, neoplasm, coma attributable to metabolic disorders or disorders of fluid or electrolyte balance, CNS vasculitis or infection, and peripheral neuropathy).
In our baseline data set 96% of those who reported a stroke had a clinical diagnosis, 81% from a specialist. However, neuroimaging will not routinely be available, and we cannot be confident that we will have enough information to attribute stroke sub-type with confidence. Silent brain infarctions (picked up by neuroimaging without clinical symptoms and signs) will not be included.
Risk exposures and covariates
Exposure data comprises
Data directly available from the baseline survey
Reassessment of self-reported variables prone to change
Reassessment of biological variables prone to change
New retrospective exposure data (not collected at baseline)
New genetic analyses
New biochemical analyses
1. Directly available from the baseline survey
Resting systolic and diastolic blood pressure, self reported hypertension, age at diagnosis and treatment
Fasting glucose, self reported diabetes, and treatment (none/ diet only/ oral hypoglycaemics/ insulin)
Waist circumference, hip circumference, height, leg length and skull circumference
Fasting total cholesterol, HDL cholesterol, triglyceride
Albumin and total protein
Full blood count and differential
Diet (intake of meat, fish and vegetables; food insecurity), exercise and activity
Smoking (pack years), drinking (current and in early/mid-life)
2. Reassessment of self-reported exposures prone to change
Living arrangements, marital status, socioeconomic status
Social network and support, life events including bereavement
Smoking, drinking, diet, activity
Self-reported diagnoses, and treatment for hypertension and diabetes
3. Reassessment of biological measures prone to change
Pulse, resting blood pressure
Waist circumference and hip circumference
Walking test
4. New retrospective exposure data (not collected at baseline)
Number of remaining teeth, use and quality of dentures
Use of lipid-lowering agents
Calf circumference
Weight (using digital scales)
Grip strength
5. New genetic analyses
By the end of the programme, DNA will have been collected and extracted from all seven centres. APOE genotyping will be conducted on all samples, and 60 SNPs informative for African/European ancestry admixture will be genotyped from centres where admixture is relevant (Cuba, Dominican Republic, Mexico, Peru and Venezuela). The 60 SNPs will be chosen from the panel assembled by Dr Mark Shriver at Penn State and Mike Smith at NCI. With 60 SNPs that have average 40% information content for ancestry, we shall be able to estimate three-way individual admixture proportions with a standard error of less than 0.1. To complete these tasks we will
make a DNA collection from saliva in China (not collected at baseline because of cultural concerns regarding phlebotomy)
extract DNA in China, Peru, Mexico and Dominican Republic
carry out APOE genotype in China, Venezuela, Peru, Mexico and Dominican Republic
carry out SNP genotyping in Venezuela, Peru, Mexico and Dominican Republic
6. New biochemical analyses
Fresh frozen serum from baseline collections are available in Cuba, DR, Venezuela, Peru, Argentina and Mexico. We will use these to investigate associations between micronutrient deficiency and dementia/ AD. We will use a nested incident case control design whereby for each incident case, we shall select three controls at random from among those matching for age, gender and education, who were free of dementia at the time of onset for the case. Assuming 219 incident cases in these six centres (see below) this will imply 876 samples to be assayed for
Vitamin B12
Folate
TSH and T4
Routine assays will be carried out by local laboratories, but procedures will be standardised as far as possible. Fresh frozen serum stored at -20C is appropriate for these analyses.
Care arrangements, dependency and indices of caregiver strain
use of health and social services over the interval between assessments
current disability and functioning (the WHODAS II)
care arrangements (informal care inputs)
for all those for whom care has been provided we will reassess caregiver economic, practical and psychological strain
burden of interview
Participant interview 60-90 minutes
Participant physical examination 10-20 minutes
Informant interview 20-40 minutes
Data Management
In Cuba, all data will be collected directly onto laptop computers using computerized questionnaires driven by epi info (version 6.01) software. These questionnaires, developed by the 10/66 group incorporate conditional skips, and interactive checking of data consistency. In the other centres, all data will be collected onto paper and transferred onto the same epi info files that are used in Cuba, but on this occasion used only for data entry rather than as computer driven questionnaires for field research. Data files will be transmitted regularly by e-mail to the IoP and backed up on our network. This scheme was used for the baseline study and worked very well.
Analyses
Much of the analysis will be conducted by local centre PhD fellows, working with/ under the supervision of UK PIs .
For incidence of dementia, person-years at risk will be calculated as the interval between baseline and follow-up assessment, or the estimated time of onset of dementia, or the time of death, whichever occurs sooner. Age-specific incidence (with Poisson standard errors and 95% confidence intervals) will be estimated for each country, by gender and age in 5-year bands by dividing number of cases by number of person-years contributed in each age band. Dementia onset is assumed to be the midpoint between the last date when known to be dementia free and the first date of dementia diagnosis (either by survey ascertainment or clinical information). A similar procedure will be used to calculate stroke attack rates.
For hypothesis testing regarding risk factors for incident dementia, mortality and stroke, we will use Coxs proportional hazards regression throughout to estimate risk associations. Informative censoring may occur through the competing risks of participants dying and becoming lost to follow-up in the interval between assessments. This problem is only rarely addressed in dementia cohort studies. We will do so firstly by verbal autopsy interviews with key informants for all deceased persons, and secondly (in a sensitivity analysis) by using proportional subdistribution hazards regression to account for informative censoring through explicit analysis of competing risks.
The ADMIXMAP program ( HYPERLINK "http://www.ucd.ie/genepi/software" http://www.ucd.ie/genepi/software) will be used to model genetic admixture. This allows for the uncertainty in estimation of individual admixture from the marker data. For this study, ADMIXMAP will be extended to support Cox regression. We shall test for
1) effects of individual admixture on dementia, AD and other outcomes
2) effects of individual admixture on the slope of relationship of APOE to dementia.
3) effects of other environmental factors or genetic polymorphisms on dementia, again controlling for population stratification.
The course and outcome of dementia and mild cognitive impairment. We will clarify the clinical course and outcome of dementia syndrome as defined by our DSM IV and 10/66 algorithms. Those 10/66 cases not confirmed by the more restrictive DSM IV criteria have tended to show equivalent cognitive and functional impairment, and behavioural problems, to those who are confirmed. This suggests good construct validity for the more inclusive 10/66 definition. Follow-up will provide prospective validation genuine dementia cases should have either progressed (cognitive and functional impairment, and need for care) or died.
9. ETHICAL CONSIDERATIONS (HYPERLINK "Guidelines, revised 180603.doc" \l "DESIGN"guidance note 9)
Participants were recruited into the original survey on the basis of informed signed consent. Persons with dementia who lacked capacity for consent were recruited on the basis of relatives signed agreement. Illiterate persons were read the information sheet and consent form, and invited to express their consent verbally, which was witnessed hence participants were not asked to sign a form they could not read. The baseline survey consent asked if the participant would be happy to contacted in few years time related to this same program. It also specified that the participant gifted the blood sample and its genetic information to the local academic institution (custodian) ceding any right to financial benefits. The custodian would decide future use of the sample within the following areas of research; dementia and AD, diabetes and other endocrine disorders, heart and circulatory disorders, hypertension, hyperlipidaemia, and common psychiatric disorders. Projects within these areas but outside of the scope of the original project would be subject to review by the local IRB. The consent specified that projects might be carried out by external researchers.
The baseline survey protocol (identical in most respects to the protocol for the follow-up surveyt) was approved for all local ethical committees and the IoP/ Bethlem/ Maudsley Research Ethics Committee (ref). Ethical approval for all secondary data analyses will be sought from KREC, and local IRBs as appropriate.
The structure and extent of health services differs between Centres. In the Cuban and in Chinese centres there are freely accessible primary care services, and specialist geriatric and psychogeriatric multidisciplinary community care teams, very much along UK lines. Thus in these countries it is be possible very straightforwardly to refer cases of clear unmet medical or social care need to the family doctor service where the project will be based. In the other countries, no such system exists/works, and many of the elderly rely much more upon private medical care providers. However, our local PIs are all well-connected senior clinicians with special interests in dementia and/ or psychiatric care. Thus it will also be possible to refer cases of clear need in all Latin American centres, as has been the practice in the baseline surveys. It should be stressed that confidentiality will not be breached, and no referrals will be made without the consent of the participant, or in cases where they lack capacity to consent, without the agreement of the family. In practice (and in our past experience) it is very unusual for that consent not to be forthcoming. Participants are often particularly keen on the health check offered by the research assessment. In the baseline survey blood pressure findings and blood test results (eg full blood count, fasting glucose, fasting lipids) have been passed back promptly to participants with recommendations for treatment (for example undetected hypertension, hypercholesterolaemia or diabetes).
10. PARTICIPANTS TO BE STUDIED ( HYPERLINK "Guidelines, revised 180603.doc" \l "SUBJECTS" guidance note 10)
10a. MALE FEMALE
Number of volunteers: 15000
Proportions of women vary between 46% and 66% by centre
Upper age limit: none
Lower age limit: 65
10b. Please provide a justification for the sample size.
Power and sample size considerations
Table 2 Incident dementia, stroke and all-cause mortality
CountryBaseline sampleDementia at baselineFree of dementia at baselineAvailable for FU interview1Person yearsDeathsIncident
dementia2Incident strokesCuba30003302670199467305095545DR20002201780132944883393730Venezuela20002001800134544903393730Mexico20002001800138129062953025Peru20002001800138129062953025Argentina20002001800138129062953025Sub-total3130001350116508811244262072219180China21621372025151351053664230TOTAL1500013001170010324295312438261210
1. assuming 6% annual mortality (GBD 2002 AMRO B mortality data, 65 and over), and 15% non-response/ non-traceability.
2. annual incidence rate of 0.0092 for all those aged 65 and over, from consensus prevalence estimates for Latin America ADDIN REFMGR.CITE Ferri20051653Global prevalence of dementia: a Delphi consensus studyJournal1653Global prevalence of dementia: a Delphi consensus studyFerri,C.P.Prince,M.Brayne,C.Brodaty,H.Fratiglioni,L.Ganguli,M.Hall,K.Hasegawa,K.Hendrie,H.Huang,Y.Jorm,A.Mathers,C.Menezes,P.R.Rimmer,E.Scazufca,M.2005/12/17AgeAgedAlzheimer DiseaseAlzheimer's diseaseconsensusCost of IllnessDelphi TechniqueDementiaDeveloping CountrieseconomicsepidemiologyFemaleHumansIncidenceIndiaMalemeta-analysismethodsMiddle AgedMortalitynewPrevalenceResearch Support,Non-U.S.Gov'tWorld HealthNot in File21122117Lancet3669503Lancet1(10), using DISMOD to derive incidence from prevalence and survival.
3. These centres included fasting blood samples, which are lacking in China
Power estimations were carried out using Stata 8.2 ssmenu command (Royston & Babiker) for sample size and power calculations in complex studies with failure time outcomes. Pooling the data across the six Latin American centres yields the following power (Table 3) for identification of the following effect sizes for associations with incident dementia and stroke, assuming the following prevalences of risk exposure.
Table 3
Power to detect given effect sizes (HRs) for associations between exposures with a prevalence of 10% and 20%, for the outcomes of dementia and stroke.
Minimum Hazard Ratio to be detectedPower for detecting association with 10% exposure prevalencePower for detecting an association with 20% exposure prevalence Outcome1,2DementiaStrokeDementiaStroke2.5100%99.8%100% 100%2.096.4%90.9%99.8% 98.8%1.886.0%75.8%97.5% 92.8%1.548.8% 39.3%71.0% 59.5%1. The power to detect associations with all-cause mortality approximates to 100% in each of these cells
2. As approximately 70% of dementia cases are categorised as AD, the power of detecting given associations with this outcome is very similar to that for stroke.
For the nested incident case-control study we estimate that 219 cases and 657 matched controls will be available. Given the matching, all analyses will be carried out using conditional logistic regression (Stata 8.2). For exposure prevalences ranging from 5% (lowest realistic estimate of prevalence for folate deficiency and subclinical hypothyroidism) to 40% (likely prevalence of vitamin B12 deficiency) such a comparison will have good (80%) to excellent (90%) power for detecting policy-relevant effects (Table 4).
Table 4
Minimum detectable effect size (OR) for matched incident case-control comparison
Exposure
Prevalence
Power5%
10%15%40%
80%2.42.01.81.690%2.72.22.01.7
11. SELECTION CRITERIA (HYPERLINK "Guidelines, revised 180603.doc" \l "SELECTION"guidance note 11)
All residents aged 65 and over within defined catchment areas. No exclusion criteria other than lack of consent to participate.
12. RECRUITMENT HYPERLINK "Guidelines, revised 180603.doc" \l "RECRUITMENT" (guidance note 12)
(i) Describe how potential participants will be identified: By records of names and addresses collected during the baseline survey. We hope also to trace participants who have moved away through names and addresses of close friends or family. Consent for this was obtained at baseline.
(ii) Describe how potential participants will be approached: We have kept in contact with participants in the baseline survey through radio and newspaper articles about the project, through the primary care and polyclinic centres involved in recruitment, through community dissemination workshops and, in some centres, mailings of project newsletters. There should therefore be a high level of awareness about the progress of the project into the second phase. For the follow-up, the research worker will visit each participant in their own homes to seek informed consent for the new survey. Given the very high rates of illiteracy (up to 70% in some centres) we do not feel that it would be generally appropriate to send written material in advance of this contact. We will however, use this method where feasible (e.g in high literacy centres such as Argentina)
(iii) Describe how participants will be recruited: By informed consent , or assent from next of kin if lacking in capacity
13. CONSENT HYPERLINK "Guidelines, revised 180603.doc" \l "CONSENT"(guidance note 13)
13a. Please describe the process you will use when seeking and obtaining consent.
"Text18"Each participant would be given an oral explanation about the study by our researcher. Each participant would have already received the INFORMATION SHEET explaining in simple, non-technical terms, the procedures, any potential risks and hoped-for benefits (see enclosed).The participant would be given reasonable time to consider this information and to consult others as necessary. Each participant would be asked to sign a consent form if he/she is willing to participate in the study.
A copy of the participant information sheet and consent form must be attached to this application. For your convenience proformas are provided at the end of this document. These should be filled in, modified where necessary, and attached to the end of your application.
13b. Will the participants be from any of the following groups? (Tick as appropriate)
Persons under 18 FORMCHECKBOX
Children in care FORMCHECKBOX
Those with learning disability FORMCHECKBOX
Those suffering from dementia x
Prisoners FORMCHECKBOX
Young Offenders (16-21 years old) FORMCHECKBOX
Those who could be considered to have a particularly dependent relationship with the investigator, eg those in care homes, students, employees FORMCHECKBOX
Other vulnerable groups x
How will you ensure that participants in the groups listed above are competent to consent to take part in this study? Please attach any correspondence to parents, guardians, carers, keyworkers etc.
Some of those with dementia may not be competent to consent. It is generally recognised, however, that those with dementia should not be excluded from high quality clinical or epidemiological research that seeks explicitly to add to knowledge of how to prevent, treat and palliate the condition from which they suffer. We follow the approach that we and many other research groups have used in seeking assent from the next of kin, with recruitment only proceeding if this assent is provided.
13c. Are there any special pressures that might make it difficult for people to refuse to take part in the study (e.g. are the potential participants students or colleagues of the investigator)? How will you address such issues?
No
14. PARTICIPANTS INVOLVEMENT: RISKS, REQUIREMENTS AND BENEFITS (HYPERLINK "Guidelines, revised 180603.doc" \l "RISKS"guidance notes 14)
14a. What are the potential hazards, risks or adverse effects associated with the study?
FORMTEXT N o n e
1 4 b . D o e s y o u r s t u d y i n v o l v e i n v a s i v e p r o c e d u r e s s u c h a s b l o o d t a k i n g , m u s c l e b i o p s y o r t h e a d m i n i s t r a t i o n o f a m e d i c i n a l p r o d u c t ? N o ( p l e a s e c i r c l e )
I f s o , p l e a s e p r o v i d e d e t a i l s :
1 4 c . D o e s y o u r s t u d y i n v o l v e g e n e t i c a n a l y s i s o r m a n i pulation? Yes
If so, please provide details:
Genetic analysis only, specifically:
60 SNPs informative for Africa, Amerindian and Caucasian ancestry allowing us to estimate the proportion of the participants genome that has segregated from ancestors from these ethnoracial groups. We will use these data to test the hypothesis that African ancestry is protective against Alzheimers Disease. A positive finding might then allow us (through admixture mapping) to identify regions of the genome that might contain candidate genes. Ethical approval for this element of the project has already been provided for Cuba and Brazil. We now seek approval for its application in the other admixed centres (Dominican Republic, Mexico, Peru and Venezuela)
APOE genotype, a proven genetic risk factor for dementia and Alzheimers disease the effect of this gene is currently unknown in most of the centres where we are working. We will also test for interactions between APOE genotype and cardiovascular risk factors in the aetiology of dementia.
Ethical approval for this element of the project has already been provided for Cuba and Brazil. We now seek approval for its application to Dominican Republic, Mexico, Peru, Venezuela, Argentina and China.
14d. Please list the experience of the investigators in the use of these procedures.
FORMTEXT P r o f . P a u l M c K e i g u e d e v e l o p e d m a n y o f t h e c o n c e p t s u n d e r l y i n g a d m i x t u r e a n a l y s i s , a s w e l l a s t h e s t a t i s t i c a l a n a l y t i c a l p r o c e d u r e s . H e h a s w o r k e d w i t h r e s e a r c h e r s a t P e n n S t a t e U n i v e r s i t y t o d e v e l o p t h e S N P b a t t e r y u s e d t o e s t i m a t e i n d i v i d u a l a d m i x t u r e .
1 4 e . I f m e d i c a l d e v i c e s a r e t o b e u s e d o n a n y p a r t i c i p a n t , d o t h e y c o m p l y w i t h t h e r e q u i r e m e n t s o f t h e M e d i c a l D e v i c e s D i r e c t i v e s ? ( F o r f u r t h e r i n f o r m a t i o n s e e t h e M e d i c i n e s a n d H e a l t h c a r e P r o d u c t s R e g u l a t o r y A g e n c y w e b p a g e s : H Y P E R L I N K " h t t p : / / d e v i ces.mhra.gov.uk" http://devices.mhra.gov.uk )
n/a
14f. Please describe how you would deal with any adverse reactions or untoward incidents.
The local PI will be immediately informed of any untoward incidents and the local PI will inform the programme PI Prof. Martin Prince. In the baseline survey the only problems arising were not linked directly to the surveys. In Mexico City a serial murderer of older people, impersonating a social worker caused us to interrupt field work for six months until the culprit was apprehended. In Argentina three older people were robbed at gunpoint in the country town where the project was based, one of whom had, coincidentally been interviewed the day before the robbery took place. We took steps immediately to reassure the community (through local radio and newspapers) of the bona fides of our project workers and how these could be established in cases of doubt. Security, both of participants and field research workers is a matter that we take very seriously with measures in place in all centres to maximise safety. There have been no untoward incidents involving compromises of research worker safety in nearly 15,000 interviews at baseline.
14g. Please name the locations or sites where the work will be done (room number, etc.)
Caracas, Venezuela
Santo Domingo, Dominican Republic
Canuelas, Argentina
Daxina and Beijing, China
Matanzas and Havana, Cuba
Mexico City, Mexico
Lima and Cerro Azul, Peru
14h. What is the potential for participants suffering pain, discomfort, distress, inconvenience or changes to lifestyle as a result of participation?
None, in our experience from the baseline survey
14i. Will group or individual interviews / questionnaires discuss any topics or issues that might be sensitive, embarrassing or upsetting? If so, please list these topics and explain how you will prevent, or respond to, volunteer discomfort.
No
14j. Is it possible that criminal or other disclosures requiring action (e.g. evidence of professional misconduct) could take place during the study? If yes, give details of what procedures will be put in place to deal with these issues. The information sheet should make it clear under which circumstances action may be taken by the researcher.
No
14k. Please describe any expected benefits to the research participant.
Those with dementia or depression, with their consent will be offered referral for further assessment and care. Blood test results and blood pressure readings in the baseline survey were passed back promptly to participants meaning that many undetected cases of diabetes, hypertension and hypercholesterolaemia could be treated. We are not repeating blood tests in the incidence phase but uncontrolled hypertension will be detected and participants advised appropriately.
14l. Under what circumstances might a participant not continue with the study, or the study be terminated in part or as a whole?
None envisaged
15. FINANCIAL INCENTIVES, EXPENSES AND COMPENSATION (HYPERLINK "Guidelines, revised 180603.doc" \l "FINANCIAL"guidance note 15)
15a. Will travelling expenses be given? If so, an appropriate comment should be included on the Information Sheet
No
15b. Is any financial or other reward, apart from travelling expenses, to be given to participants? If yes, please give details and justification.
No
15c. Will the study result in financial payment or payment in kind to the department or College? Please specify, including the amounts involved.
No (other than research funding as described above)
15d. If this is a study in collaboration with a pharmaceutical company or an equipment or medical device manufacturer, please give the name of the company and indicate what arrangements exist for compensating patients or healthy volunteers for adverse effects resulting from their participation in the study (in most cases the Committee will only approve protocols if the pharmaceutical company involved confirms that it abides by ABPI (The Association of the British Pharmaceutical Industry) guidelines). A copy of the indemnification form (appendix B) should be submitted alongside this application.
No
16. CONFIDENTIALITY, ANONYMITY AND DATA STORAGE (HYPERLINK "Guidelines, revised 180603.doc" \l "STORAGE"guidance notes 16 and 17)
What steps will be taken to ensure confidentiality (including the confidentiality and physical security of the research data)? Give details of the anonymisation procedures to be used, and at what stage they will be introduced.
Paper data records are promptly entered into computerised data files (stored locally and backed up on the Institute of Psychiatry server). Paper records are kept locked in secure locations. The key files containing names and addresses linked to ID code numbers are kept separately. The archived data files (for analysis, and according to Wellcome Trust grant conditions to be made available for monitored access to the wider scientific community) include the ID numbers but not the personal identifiers and are therefore effectively anonymised.
16b. Who will have access to the records and resulting data?
Local PIs, and London IoP based project team (Prof. Prince, Dr Ferri, Dr Albanese and Ms Sousa). We have established an international steering group for determining the bona fides of research groups seeking access to the data, and to review the scientific quality of their proposals. Any such proposals would be referred for separate ethical approval to KCL and local ethical committees.
16c. Where, and for how long, do you intend to store the consent forms and other records?
In the local centres, for 10 years.
17 INFORMATION SHEET AND CONSENT FORM (HYPERLINK "Guidelines, revised 180603.doc" \l "INFORMATION"guidelines 17 and 18)
The information sheet for participants on the next page should be composed according to the guidelines and submitted alongside this protocol. The text in red should be deleted or modified as appropriate. If the language in this template is not suitable for your intended target group it may be modified. You should also submit a copy of the consent form which should be created using the template provided. Details of how these documents should be used are provided in the guidelines.
The following, where applicable, are attached to this form (please tick):
[ ] Participant Information Sheet
[ x ] Consent Form
[ ] Appendix A relating to medical products
[ ] Appendix B Certificate of Indemnity (for pharmaceutical company collaborators)
[ ] Appendix C relating to studies involving radiation (available separately; HYPERLINK "http://www.kcl.ac.uk/research/crec/radiation.doc" www.kcl.ac.uk/research/crec/radiation.doc)
[ ] Letter to general practitioners
[ ] Letter to parents/guardians/key carer/social services
[ ] Letter of ethical committee approval or other approvals
[ ] Copy of email recruitment circular/poster/press advertisement.
[ ] Questionnaire/ topic guide/ interview questions
[ ] Evidence of permission from organisation (i.e. school, company, shop) where research is to take place
INFORMATION SHEET FOR PARTICIPANTS
REC Protocol Number............
YOU WILL BE GIVEN A COPY OF THIS INFORMATION SHEET
Cardiovascular risk, nutrition and dementia incidence and dementia incidence in admixed populations undergoing rapid health transition Latin America and China
We would like to invite you to participate in this original research project. You should only participate if you want to; choosing not to take part will not disadvantage you in any way. Before you decide whether you want to take part, it is important for you to understand why the research is being done and what your participation will involve. Please take time to read the following information carefully and discuss it with others if you wish. Ask us if there is anything that is not clear or if you would like more information.
In x (name of country) people are living for longer, and having fewer children. Diseases linked to ageing for example heart disease, stroke, and dementia are becoming more common. Dementia is a word used by doctors to describe problems with memory, concentration and thinking if they become serious enough to affect day to day life. This is a problem that affects older people in particular; around one in 20 of all those aged 65 years and over. It can be caused by several different disease processes, the commonest of which is Alzheimers Disease. We are keen to understand more about dementia, stroke, mental health and general health, particularly from those parts of the world, like x (name of country), where the health of older people has been little studied. We hope to find out how common dementia and stroke are in x. We are interested in the impact of psychological and physical health conditions on the arrangements available for the care and support of the older people. Finally we are also interested in finding out more about the underlying causes of dementia, both the effect of how we live our lives, and genetic factors which we are born with and can be inherited. For Dominican Republic, Venezuela, Mexico, Peru [Specifically we are testing whether older people with more African ancestry in their genetic make up are protected against dementia, and the effect of the Apolipoprotein E gene on risk for dementia].
Section to be inserted for China only
[For the genetic part of the study we will be comparing the genes in the saliva of people with dementia to others without dementia. This part of the study may lead to increased understanding of what causes dementia and may in the future lead to tests for dementia. However the result of the genetic study on any one individual will not tell us whether they or their relatives are at risk of getting any disease. For this reason we will keep the results anonymous and will not be able to give you, or anyone else, any information about your genes. By agreeing to the saliva sample, you will be making a gift of it, and the genetic information contained within it to the Peking University, Institute of Mental Health where it will be stored. They will decide how this sample will be used in the future. In addition to genes for dementia, the sample may later be used to study genes for
1) diabetes and other endocrine disorders (disorders of glands)
2) heart and circulatory disorders
3) hypertension (high blood pressure)
4) hyperlipidaemia (raised blood fat levels)
5) depression and other common psychiatric disorders
The Ethical Review Board that helps protect your rights during this research project will need to review and approve all future projects in these areas. Without this specific approval, the studies cannot and will not happen. Some of these projects may be carried out by researchers other than those who ran the first project, including researchers working for commercial companies. We will not give these other researchers any information that would allow them to identify you. By making the gift of this sample to the Peking University, Institute of Mental Health you will also be giving up any right to share in any financial benefits from scientific discoveries that may follow.
We will not carry out any studies outside of the areas described above without your specific consent. Therefore, if we wanted to extend the scope of our studies to some new area, we would have to approach you again to ask your permission, and we would also need to get the approval of the Ethical Review Board. Without your consent, and the ethical approval, these studies cannot and will not happen.
Who can take part in the study?
You kindly took part in the first phase of this study three years ago. We are now recontacting all 2000 people all aged 65 years and over, living in x who took part in the first phase. Our aim in this second phase of the study is to look at any changes in health, and to find out what factors are associated with good and bad health.
What will the study involve?
A researcher will visit you in your own home, at a time that you arrange to suit your convenience. As in the first phase of the study, the researcher will have questions to ask about your health and general circumstances, and about experiences in your life up till now. This will take 90 minutes (one hour and a half). In a separate appointment, a nurse will visit to check your height, weight, and blood pressure and other aspects of your physical health. This will take 15 minutes. We will also ask you to identify for us a family member or friend, who knows you and your current circumstances well. The researcher will also have some questions for them, and this interview will last between 20 and 40 minutes. The reason for this interview, is that sometimes it helps to have another persons view of how an older person has been coping, and about any changes in their health.
Confidentiality
All of the information that you provide will be kept confidential. Your individual responses to questions, and the observations made by the researcher will be stored in an anonymised data set (which means that they cannot be linked to your personally). The published reports from the study will summarise information across the study sample as a whole, and will not contain information about individuals. This section will vary from centre to centre depending upon local arrangements [We can provide you, if you would like us to do so, information about your health from the examinations that were carried out. If necessary, we may advise you to contact and doctor, and can help with this if you would like us to do so].
FORMTEXT F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T
I t i s u p t o y o u t o d e c i d e w h e t h e r o r n o t t o t a k e p a r t . I f y o u d o d e c i d e t o t a k e p a r t y o u w i l l b e g i v e n t h i s i n f o r m a t i o n s h e e t t o k e e p a n d b e a s k e d t o s i g n a c o n s e n t f o r m . I f y o u d ecide to take part you are still free to withdraw at any time up to the completion of the study and finalisation of the data set, without giving a reason.
CONSENT FORM FOR PARTICIPANTS IN RESEARCH STUDIES
Please complete this form after you have read the Information Sheet and/or listened to an explanation about the research.
Title of Study: ___________________________________________
Kings College Research Ethics Committee Ref:________________
Thank you for considering to take part in this research. The person organizing the research must explain the project to you before you agree to take part.
If you have any questions arising from the Information Sheet or explanation already given to you, please ask the researcher before you decide whether to join in. You will be given a copy of this Consent Form to keep and refer to at any time.
I understand that if I decide at any other time during the research (up to the completion of the study and finalisation of the data set) that I no longer wish to participate in this project, I can notify the researchers involved and be withdrawn from it immediately.
I consent to the processing of my personal information for the purposes of this research study. I understand that such information will be treated as strictly confidential and handled in accordance with the provisions of the Data Protection Act 1998.
Participants Statement:
I _____________________________________________________________________
agree that the research project named above has been explained to me to my satisfaction and I agree to take part in the study. I have read both the notes written above and the Information Sheet about the project, and understand what the research study involves.
Signed Date
Investigators Statement:
I _____________________________________________________________________
confirm that I have carefully explained the nature, demands and any foreseeable risks (where applicable) of the proposed research to the volunteer.
Signed Date
INFORMATION SHEET FOR RELATIVES/ INFORMANTS OF DECEASED PARTICIPANTS
REC Protocol Number............
YOU WILL BE GIVEN A COPY OF THIS INFORMATION SHEET
Cardiovascular risk, nutrition and dementia incidence and dementia incidence in admixed populations undergoing rapid health transition Latin America and China
We would like to invite you to participate in this original research project. You should only participate if you want to; choosing not to take part will not disadvantage you in any way. Before you decide whether you want to take part, it is important for you to understand why the research is being done and what your participation will involve. Please take time to read the following information carefully and discuss it with others if you wish. Ask us if there is anything that is not clear or if you would like more information.
We are keen to understand more about dementia, stroke, mental health and general health, particularly from those parts of the world, like x (name of country), where the health of older people has been little studied.
Why are we contacting you now?
Your relative kindly took part in the first phase of this study three years ago. We are very sorry to hear of their recent death. We are now recontacting all 2000 people all aged 65 years and over, living in x who took part in the first phase including the relatives of those who died during this period Our aim in this second phase of the study is to look at changes in health before death (and causes of death) and to find out what factors are associated with good and bad health.
What will the study involve?
A doctor will visit you in your own home, at a time that you arrange to suit your convenience. They will have questions to ask about your relatives health and any illnesses they may have had, particularly in the period leading up to their death. This will take approximately 45 minutes .
Confidentiality
All of the information that you provide will be kept confidential. Your individual responses to questions, and the observations made by the researcher will be stored in an anonymised data set (which means that they cannot be linked to your personally). The published reports from the study will summarise information across the study sample as a whole, and will not contain information about individuals.
FORMTEXT F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T F O R M T E X T
I t i s u p t o y o u t o d e c i d e w h e t h e r o r n o t t o t a k e p a r t . I f y o u d o d e c i d e t o t a k e p a r t y o u w i l l b e g i v e n t h i s i n f o r m a t i o n s h e e t t o k e e p a n d b e a s k e d t o s i g n a c o n s e n t f o r m . I f y o u d ecide to take part you are still free to withdraw at any time up to the completion of the study and finalisation of the data set, without giving a reason.
CONSENT FORM FOR RELATIVES/ INFORMANTS IN RESEARCH STUDIES
Please complete this form after you have read the Information Sheet and/or listened to an explanation about the research.
Title of Study: ___________________________________________
Kings College Research Ethics Committee Ref:________________
Thank you for considering to take part in this research. The person organizing the research must explain the project to you before you agree to take part.
If you have any questions arising from the Information Sheet or explanation already given to you, please ask the researcher before you decide whether to join in. You will be given a copy of this Consent Form to keep and refer to at any time.
I understand that if I decide at any other time during the research that I no longer wish to participate in this project, I can notify the researchers involved and be withdrawn from it immediately.
I consent to the processing of my personal information for the purposes of this research study. I understand that such information will be treated as strictly confidential and handled in accordance with the provisions of the Data Protection Act 1998.
Participants Statement:
I _____________________________________________________________________
agree that the research project named above has been explained to me to my satisfaction and I agree to take part in the study. I have read both the notes written above and the Information Sheet about the project, and understand what the research study involves.
Signed Date
Investigators Statement:
I _____________________________________________________________________
confirm that I have carefully explained the nature, demands and any foreseeable risks (where applicable) of the proposed research to the volunteer.
Signed Date
19. AUTHORISING SIGNATURES
19. AUTHORISING SIGNATURES
The information supplied above is to the best of my knowledge and belief accurate. I have read the notes to investigators and clearly understand my obligations and the rights of subjects/study participants, particularly in so far as to obtaining valid consent.
Signature of Principal Investigator
..Date
Name of Head of Department: FORMTEXT
S i g n a t u r e o f H e a d o f D e p a r t m e n t
& & & & & & & & & & & & & & & & & & & & & & & & & & & & & . . D a t e & & & &
N a m e o f M e d i c a l S u p e r v i s o r ( i f a p p r o p r i a t e ) : F O R M T E X T
M e d i c a l S u p e r v i s o r s M D U / M P S ( o r o t h e r i n s u r a n c e p r o v i d e r ) n u m b e r : F O R M T E X T
S i g n a t u r e o f M e d i c a l Supervisor (if appropriate)
..Date
Communications about this application should be addressed to:
Name: ........................................................................................................................
Address: (full postal address please)
.................................................................................
....................................................................................................................................
Telephone No: ..........................................................................................................
Fax No: ......................................................................................................................
Email: ......................................................................................................................
Please note that correspondence regarding the application will normally be sent to the Principal Investigator and copied to other named individuals if required.APPENDIX A: DETAILS OF MEDICIAL PRODUCTS
Please state name, dose, number of doses of the substances to be administered, and the route of administration.
n/a
Please state briefly the known pharmacology of any pharmacologically or physiologically active substances, including possible side effects. Please provide appropriate documentation.
n/a
REGULATORY STATUS
If the study involves the administration of medicinal products to participants, please indicate which of the following is applicable and append a copy of the relevant documentation or in the case of the exemptions, a copy of the letter from the Medicines and Healthcare Products Regulatory Agency confirming exemption.
a) Marketing Authorisation (previously called a Product licence)
b) Clinical trial authorisation (CTA)*
*The CTA replaces the CTC (Clinical Trial Certificate), CTX (Clinical Trial Exemption) and DDX (Doctors and dentists exemption scheme). Further information on this can be found on the Medicines and Healthcare Products Regulatory Agency website: HYPERLINK "http://medicines.mhra.gov.uk" http://medicines.mhra.gov.uk
The Committee will only give approval on presentation of the relevant certificate or letter confirming authorisation or exemption.
APPENDIX B: INDEMNITY FOR COMMERCIAL COLLABORATORS
Approval will only be given to drug company-sponsored research projects where the company concerned has agreed to accept the ABPI Guidelines for compensation, under which the sponsoring company undertakes to compensate volunteers who may be harmed without the necessity for the patient or volunteer first to prove negligence.
CERTIFICATE OF INDEMNITY
The text of a certificate of indemnity is given below, but the suitability of any such certificate must always be checked with the appropriate College officer.
The Company will indemnify and hold harmless King's College London, and also the authorised investigator(s) employed in the service of the said College from and against any and all third party claims and suits for injuries and damages caused by the administration during the course of the clinical investigation and in accordance with the Protocol (a copy of which is attached hereto) of the company's product designated as (the said product) and supplied to the authorised investigator by the company for the purpose of the clinical investigation described in the attached protocol.
a) that nothing herein shall be interpreted as an indemnity by the company in respect of claims and suits for injury and damages caused by the failure of the said College and/or the authorised investigator(s) to observe all proper and reasonable standards in the use of the said product according to the Protocol, and
b) that immediately upon notice of any kind whatsoever of any claim or law suits the said College will notify the company in writing thereof and will permit the company's lawyers, at th ( ) * H I 6 V M
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