A joint research collaborative study between University of Pittsburgh and SHARE INDIA - MIMS is approved by the Health Screening Committee of ICMR, GoI
I. Introduction and Brief Background
The increase in the older population is most rapid in developing countries and in the oldest old. There is a need for more detailed data on the prevalence and causes of disability in these countries and also an opportunity to better understand the causes and consequences of disease by examining cross-cultural differences. The Indian population is not well described, but evidence suggests that the current demographic transition provides a unique opportunity to better understand the potential for future disability. Our goal is to establish a longitudinal cohort study in India to define the prevalence, incidence and risk factors for disability and age-related disease in the population of older adults (60+) in the Telangana region near Hyderabad.
Population: We plan to enroll 500 men and women aged 60 years and over into the Mobility and Independent Living in Elders Study (MILES). Based on the previously conducted REACH survey, we estimate that there are approximately 3302 in the selected region. Prior to recruitment, we will conduct information sessions in the community to describe the study and determine acceptability. We will begin with recruitment and a screening interview attempting to include a random sample of 500 individuals from 28 villages in the REACH area. For those who consent and are screened as eligible, we will enroll them for a full baseline examination, which includes interview, examination and a blood sample for lipids, anemia screen, fasting glucose. We will then contact enrolled participants annually for evaluation of mobility impairment and mortality.
The study will be conducted in collaboration with the REACH program (Rural Effective Affordable Comprehensive Health Care) conducted by SHARE/MediCiti, a hospital and medical school complex founded in Hyderabad, India by Dr. P.S. Reddy, Department of Cardiology, University of Pittsburgh. The REACH Project has enumerated all households and household members, and mapped each dwelling by Geographic Position Sensors (GPS). A detailed database is maintained.
REACH is a model of universal, comprehensive rural health care that provides health education, immunizations, antenatal care and primary to tertiary care for a population of 48,000 in 40 villages in the Ranga Reddy District on the northern outskirts of Hyderabad in the state of Telangana, India. Local residents with at least an eigth grade education are trained by MediCiti staff and charged with the task of visiting each home in their assigned territory at least once a month. These Community Health Volunteers (CHVs) collect birth and death data, maintain a register of pregnant women and encourage them to seek antenatal care, maintain a register of immunizations, provide one-to-one health education and preventive counseling, support MediCiti's tuberculosis screening program and arrange for follow-up at the nearest health center.
The REACH Project has been used to recruit for the Longitudinal Indian Family Health Study, the LIFE study, a parallel study to the Pittsburgh National Children’s Study, which seeks to enroll couples planning to conceive and follow their children developmentally. For that study, a team of research staff has been trained to do interviewing, blood sampling and anthropometric measures. This same team will conduct the MILES Study.
Eligibility: The goal of the MILES Study is to survey and enroll as many of the members of the older population as possible, therefore, there will be few exclusions. Eligibility criteria include being age 60 years or over, able to give informed consent (functional vision, hearing and cognitive function), no plan to move from the area over the next 5 years and no end stage diseases such as terminal cancer.
Consent: All consent forms and questionnaires will be translated into Telugu and administered by native Telugu speakers. Physical measurements will be taken by a same-sex field worker.
Data collection summary: After consent is obtained, the first visit will begin and will be comprised of an interview that will take approximately 2 hours. Within the subsequent two weeks, a fasting blood draw will be scheduled to be obtained at the home by a staff phlebotomist. Participant time will be 15 minutes. A third appointment will be scheduled at the MediCiti Hospital research center and will include a physical examination including performance-based measures of physical, cognitive function and non-invasive testing. The physical examination portion will take approximately 2 hours.
As noted, same sex examiners will be used for physical measures. This length of data collection is typical of studies of older persons and well tolerated. All procedures will be reviewed by a participant advisory panel for cultural sensitivity and pre-tested before fielding the study. No data will be recorded in the pre-testing process.
Interview: The interview will include life events, demographics, physical function and activity, medical and personal history of smoking, diet and social environment, depression symptoms and medication use. This will take approximately 2 hours. The questionnaire is based on the World Health Organization’s aging study, called SAGE.
Biological samples: The biological sample team (two females or one male, one female) will visit the home to collect peripheral blood from a vein in the participant’s antecubital fossa using new vacutainers and new needles. In preparation, the interviewer would have given each participant instructions to fast after 10:00 pm the evening before the visit. Three tubes, (30 cc, or 2 tablespoons) will be collected and run for lipids, fasting glucose, hemoglobin and hematocrit. The participants will be given the results of their tests. Clinically abnormal values will be discussed with the participant and if not previously known or under care, arrangements will be made for referral to a physician at the MediCiti Hospital.
Research clinic visit: An appointment and transportation will be arranged for 2-6 participants to come to the MediCiti research center (up to one hour travel time, average 45 minutes). Transportation will be provided by a staff member using a SHARE research vehicle. Research staff will first measure weight, height, waist and hip circumferences, blood pressure and heart rate, tests of cognitive function, and performance-based measures of walking and grip strength. Walking speed will be assessed with a stopwatch over a 4 meter course. Ability to rise from a chair will be assessed for lower extremity function. Grip strength will be assessed in both hands with a handheld isometric dynamometer. Cognitive tests will include a verbal recall test and digit span forwards and backwards. These are standardized memory tests that do not require ability to write and are being used in the WHO SAGE project. Blood pressure will be measured three times using the standard aneroid blood pressure equipment. Anthropometric measurements include height using a portable stadiometer; weight using a portable calibrated scale; waist circumference at the umbilicus; and hip circumference. Non-invasive tests include electrocardiogram (ECG), spirometry (pulmonary function), carotid ultrasound, Doppler ultrasound (ankle – arm index), and peripheral quantitative computerized tomography (pQCT) of the radius and tibia for bone density, geometry and strength, and muscle density. The ECG, spirometry, Doppler ultrasound and carotid ultrasound are conducted with small, portable hand-held digital devices. The pQCT uses a small low-dose scanner that does not require radiation shielding, but is not portable. Each of these tests will take 20-30 minutes for a total of an additional 2 hours. With transportation, participant time will be up to 4 hours. A meal will be provided at no charge to the participant.
Follow-up: We will contact the participants annually to update medical history and obtain estimates of outcome rates. The primary outcomes of interest is mobility disability. We will estimate rates of incident MI, stroke, cancer, COPD, diabetes, hypertension, incident ADL disability, cognitive impairment, and mortality for future expansion of the study. We will ask that each participant designate two family members or friends who can serve as proxy informants in the future should the participant become impaired. If the participant is not able to be interviewed, the informant will be asked about the participant’s functioning and recent medical history. For participants who die between annual contacts, the designated informants will be interviewed about the circumstances of the death.
The sample size is adequate for our specific purposes. We are requesting permission to collaborate on this pilot study of 500 to gain firm estimates of the prevalence of disabling diseases in this community and to establish our ability to engage and follow this rural population.
With this sample size we will be able to estimate disease or disability prevalence within ±2.6% to ±4.3% if the true prevalence is in the range of 10—40%. We will be able to determine associations between performance measures of function and disease as follows:
Table 1: Power to detect cross-sectional associations between diseaseand performance based on baseline sample size of 500
|
Disease prevalence |
|||
10% |
20% |
30% |
||
Measurement |
Mean (SD)for older adults |
Difference Detectable with 80% Power |
||
Gait speed |
1.17 (0.24) m/s |
0.11 |
0.08 |
0.07 |
Grip strength |
32.8 (7.1) kg |
3.3 |
2.4 |
2.1 |
Digit symbol test |
35.2 (14.8) |
6.8 |
5.1 |
4.3 |
Power for longitudinal follow-up will also be adequate because the rates of mobility limitation are expected to be high.
Table 2. Hazard ratios detectable with 80% power for mobility limitation, based on rate of 40% by year 5 and sample size of 400 without mobility limitation at baseline (assuming exclusion of 100 cases with mobility disability at baseline and censoring for mortality).
| Risk factor prevalence | Hazard ratios detectable with 80% power |
| 10% | 2.09 |
| 20% | 1.74 |
| 30% | 1.62 | 40% | 1.57 |
These hazard ratios correspond to increases in risk of 57-109% for common chronic conditions which are expected to range in prevalence from 10-40%. For continuous variables, we would compare the worst quintile (20%) to the upper quintiles, which corresponds to the estimates for disease prevalence of 20%. Power for continuous risk factors would be greater.
IV. Significance
There has been a recent unprecedented increase in the world’s population of older adults, with a projection of a doubling from 7 to 14% in the next 30 years. The rate of growth in developing countries is double that of developed countries and is also twice as great as that of the total population. In 2008, 313 million or 62% of the world’s population over 65 years lived in developing countries with 166 million in India and China. In the next 30 years, the growth of the Indian population over 65 years is expected to reach 222 million. In the next ten years, the proportion of older people will exceed the proportion under age 5 years for the first time in human history. This remarkable achievement will cause considerable social and economic challenges because of the high burden of chronic disease related to aging. Additionally, as seen in Mexican-Americans and Native Americans, the epidemiological transition towards less activity and higher caloric intake will likely shift this burden even higher in older adults who are currently living through this transition. Much has been learned about the importance of the epidemiological transition in India. Diabetes prevalence has increased dramatically along with concomitant hypertension and subsequent cardiovascular disease. These factors are expected to have adverse consequences on future cognitive function and mobility impairment in older adults.
There are three large cross-national efforts that have emerged in the past 10 years to provide data to address these concerns. These include a Survey of health and Retirement in Europe (SHARE), modeled on English Longitudinal Study of Ageing (ELSA) and the US Health and Retirement study (US HRS). SHARE is designed to include all 27 members of the EU in 2008. These projects include surveys of health and disability, but focus on socioeconomic factors related to retirement. The INDEPTH project, International Network for the Demographic Evaluation of Populations and their Health, includes 37 sites in Africa, Asia and Latin American and is designed to provide adult mortality data that is otherwise lacking. The WHO recently launched the Study of Global AGEing and Adult Health (SAGE) in 6 countries, including China, Ghana, India, Mexico, Russia and South Africa. It is modeled on the SHARE project and will also link to INDEPTH. These studies will provide demographic data but are not designed for in depth study of disease prevalence, causes of disability or explore mechanisms. In Asian populations, there are important biological differences in age-related chronic disease with differences in risk factors and potential differences related to genetic factors as well. Thus, it is important that each region of the world conduct studies to identify the factors that are unique to that region.
V.Risks and Benefits
At the examination, a blood sample will be required. The risks associated with the drawing of a blood sample are discomfort at the site of needle insertion, bruising (black and blue discoloration) at the site and rarely dizziness, fainting or infection. However, it should be noted that all study personnel who draw blood, as well as perform any other required tests, are experienced, well trained and certified. There are established "alert values" for each lab test; blood results that are outside of the "normal range" will be flagged and reported to the study physicians on a weekly basis and forwarded to the study participant or their physician if requested and clinically indicated. The standardized procedure for establishing a safe and appropriate location and method for obtaining human blood and human blood products for research purposes will be followed in the home of the participant.
Participation in the pQCT study procedure involves exposure to radiation. The equipment does not require special shielding. The amount of radiation exposure associated with these procedures is addressed in the table below. (Note: a mrem is a unit of radiation dose).
Exposed* Procedure Study
forearm forearm 10 mrem 3 (a slice or view)
For comparison, radiation workers are permitted, by US federal regulation, a maximum whole body radiation exposure of 5,000 mrem or a maximum single organ radiation exposure of 50,000 mrem per year. There is no minimal level of radiation exposure that is recognized as being totally free of risk of causing genetic mutations or cancer. However, the risk associated with the radiation exposure received from participation in this study is considered to be low and comparable to everyday risks.
The benefits to the person who participates in this study are assessments of blood pressure, blood sugar, lipids, and of general state of health, and contact with persons who can be of aid in finding other health care when necessary. Clinically abnormal values will be discussed and participants counseled to seek medical care. The information gathered in this study will be very important for scientists to learn more about what factors might be important in developing disability in this population.
Information obtained from this research, including history, laboratory data, findings on physical examination, biopsy or surgery will be kept strictly confidential. Clinically abnormal results will only be shared with a health professional or family member with documented permission of the participant. A participant identification number will be used when sending and analyzing data rather than his/her name. Also, all data will be kept in a locked room. Data collected will be stored in computer databases by ID only. All computers will be locked and password protected. Participant records will be kept until all data analyses are completed and then the records will be destroyed.
The MILES Study is an observational study; therefore no interventions will be conducted.
VI. Data and Safety-Monitoring Plan
Overview: A local meeting will be held monthly, at which Dr. Balasubramanian, Project Director and the field staff act as a continuing local review committee for study activities and participant safety. The safety and monitoring plan will be overseen by Dr. K. Govind Narsingrao, MD, Principal Investigator and Medical Monitor. Monitoring will be on a quarterly basis, or more frequently should unanticipated problems be noted. The following information will be submitted to the IRB at time of obtaining annual renewal approval of the research protocol. 1.) The frequency of monitoring that took place during the renewal interval and/or the date(s) that data and safety monitoring was conducted. 2.) A summary of cumulative adverse event data including a retrospective assessment of experimental intervention causality. 3.) A summary of the assessment that was performed to evaluate external factors of relevant information that may have an impact on the safety of the study participants or the ethics of the research study. 4.) A summary of the outcomes of procedural reviews conducted to ensure subject privacy and research data confidentially. 5.) Final conclusions regarding changes to the anticipated benefit-to-risk ratio of study participation and final recommendations related to continuing, changing, or terminating the study. If recommendation is made to change the research study, an adequate rationale for this decision will be provided.
Medical monitor Dr. K. Govind Narsingrao has agreed to serve as medical monitor. He is principal investigator and a faculty physician at MediCiti Hospital and Medical School and is able to provide or oversee medical care to research subjects for conditions that may arise related to the conduct of the study. He will monitor subjects during the conduct of the study. He will review all tests with clinical abnormal values and assist staff in arranging for medical care at MediCiti Hospital.
Data Sharing Authorized representatives of the University of Pittsburgh or the Indian government may review study information, which may include participants' identifiable medical information, for the purpose of monitoring the appropriate conduct of this research study, or if required to by a court of law. Authorized representatives may view data/documents, with personal identifiers, associated with the conduct of the research study if required for the official review/court order. Authorized representatives will be asked to maintain the confidentiality of the data. If personal identifiers are not officially required, only de-identified data/documents will be provided to authorized representatives.
With the approval of the PIs of the study, secondary investigators will be allowed to use biological samples (without personal identifiers) and relevant data (without personal identifiers) to collaborate or conduct studies which fall within the specific aims of the current study. For any study which falls outside the specific aims, or for which the PIs concur that use of identifiable data is necessary, it will be necessary to obtain a new consent from the participants to do so.
All forms will be barcoded and the barcode scanned at the beginning of data entry. Names and other identifying data will be included on the Checklist Form for each visit to enable verification of identity of participants and to facilitate visit and participant management. After each visit is completed, the Checklist Form will be removed and stored separately. These data will be kept in a separate Participant Management database which will not contain other types of data. The questionnaires which go to the data entry process will be identified only by the barcoded ID. Names will not be entered into the data analysis files. Participants will be identified only by ID number. All paper questionnaires and consent forms will be stored in a locked file room.
All the samples collected will be identified only by bar coded labels which will include coded ID Number and study visit date. Other than the barcoded ID, there will be no personal identifiers on the sample labels.
VII. Costs and Payments
Although the research staff will not be able to provide care for other conditions, we will help find care for such conditions if possible. There are no charges for the examination, the laboratory work or other tests. Individuals who have a fasting blood glucose test will be provided a small meal or snack.
VIII. Qualifications of Investigators:
Principal investigator:
K. Govind Narsingrao, MD is an Associate Professor in Community Medicine at the MediCiti Institute of Medical Sciences. He is trained in Family and Preventive Medicine. He will also serve as medical monitor.
Co-principal Investigator
K. Vijayaraghavan, MBBS, MSc is the director of the SHARE India Research Institute to serve as Co-PI to strengthen the local leadership for the project. He will mentor the Principal Investigator and other junior investigators in the development of research skills and in implementation of the MILES Study. Dr. Vijayaraghavan is an expert in community medicine and nutrition research. He is a senior investigator with a distinguished career in community health research. Dr. Vijayaraghavan brings a wealth of community-based research experience to the MILES Study. As Head, Division of Field Studies (Retired), National Institute of Nutrition, he conducted community based research for 39 years. He has 132 publications including: 64 serial & peer reviewed publications, 64 books and chapters, 44 technical reports, and 8 consultancy reports. He is the Director of the SHARE INDIA Research Institute. Under his leadership as Project Director for the REACH Project, SHARE India has developed a system of outreach to the rural population based on a backbone of Community Health volunteers, one in each small village, two in larger villages. Through the work of the CHVs and outreach staff from SHARE, the population of 43,000 has been censused, and the household structure and GPS location of each home recorded. The main goal of the REACH Project is to identify the best methods for implementation of health care services in the population. For example, the REACH project has demonstrated successful population-based implementation of a system in which 96% of children aged of 12-24 months were completely immunized for BCG, measles, and 3 doses each of each of polio/DPT, as compared to only 43% in the Indian National Family Health Survey-3.
Co-investigators:
K. Balasubrahmanian, PhD, Associate Director (Research), SHARE INDIA, is a demographer with experience in administering very large population-based studies in India. He will serve as the project director.
P.S. Reddy, MD is the Chairman, SHARE INDIA, Hyderabad, India, and plays a major role in the development and administration of research projects conducted by SHARE. He also has been a highly esteemed member of the University of Pittsburgh Medical School faculty for the past 40 years.
B. Aparna Varma, MD is Professor and Chair of Biochemistry at the MediCiti Institute of Medical Sciences with expertise in biochemical markers of osteoporosis and cardiovascular disease.
T.Kamaraju,M.B.B.S is tutor in community medicine at the MediCiti Institute of Medical Sciences. He has been working in this institute for the past 5 years.
Enakshi Ganguly, MD, is an Assistant Professor, in Community Medicine at the MediCiti Institute of Medical Sciences. She has wide research experience and worked on various projects funded by the NIFHW, NNFPA, USAID etc.
Pawan Kumar Sharma, MD, is an Assistant Professor, in Community Medicine at the MediCiti Institute of Medical Sciences. He has wide research experience and worked on various projects funded by the NIFHW, NNFPA, USAID etc.
Jammy Guru Rajesh, MBBS, MBA is Associate Director, SHARE India, PHMI. He has as wide experience in various projects funded by CDC etc.
P. Satayanarayana, MD, is Head of the the Department, Central lab at MediCiti Institute of Medical Sciences. He has been working in this institute for the past 6 years.
Tushar Singh, MD, M.Sc is a doctoral student and research associate in the Department of Epidemiology at the University of Pittsburgh. His research interests are physical and cognitive disability and subclinical cardiovascular disease. He has research experience in several large multi-center studies of aging including Cardiovascular Health Study (CHS), Osteoporotic Fractures in Men Study (MrOS) and Aspirin in Reducing Events in the Elderly Study (ASPREE).
India Consultant in Aging research:
Dr. B S Garg, M D, Ph. D., FAMS will serve as a consultant. He is Dean and Director, Dr. Sushila Nayar School of Public Health, Director-Professor of Community Medicine and Head, WHO Collaborating centre for Research & Training in Community Based Maternal, Newborn & Child health Mahatma Gandhi Institute of Medical Sciences. He is a senior investigator with expertise and publications in the issues of aging in India.
University of Pittsburgh Consultants:
Anne B. Newman, MD, MPH, is Professor of Epidemiology and Medicine, and the Director of the Center for Aging and Population Health (CAPH) in the Department of Epidemiology, University of Pittsburgh Graduate School of Public Health. She is board certified in Geriatrics and Internal Medicine. Dr. Newman’s research interests include longevity, functional aging, sarcopenia, subclinical cardiovascular disease and successful aging. She is a Co-Investigator of the Cardiovascular Health Study (CHS), a longitudinal study of the incidence and natural history of coronary heart disease and stroke in older adults since 1989. She is the Principal Investigator of the CHS All Stars Study, examining longitudinal changes in physical and cognitive function in the CHS cohort. She is the Principal Investigator of the Health and Body Composition study, a study of longitudinal changes in bone, lean and fat mass in relation to function in older adults.
Jane A. Cauley, DrPH is currently a Professor and Vice Chair of Research in the Dept. of Epidemiology at the University of Pittsburgh. She is/has been Principal Investigator of several osteoporosis studies including the male study, the Osteoporotic Fractures in Older Men Study (MrOS), Study of Osteoporotic Fractures (SOF), Fracture Intervention Trial (FIT), Postmenopausal Evaluation and Risk-reduction with Lasofoxifene (PEARL), and Raloxifene Use for the Heart (RUTH). She has extensive experience in the conduct and direction of large epidemiological cohort studies and clinical trials, especially osteoporosis studies.
Clareann H. Bunker, PhD. Dr. Bunker is an Associate Professor in the Department of Epidemiology at the University of Pittsburgh. She has over 20 years experience in conducting international epidemiology studies in Nigeria in Africa, the Virgin Islands and India. To: In 2008, Dr. Bunker collaborated with Dr. PS Reddy and colleagues at SHARE INDIA, and University of Pittsburgh colleagues, in the submission of a research grant application to ICMR and the U.S. NIH (INDO-US PROGRAM ON MATERNAL AND CHILD HEALTH AND HUMAN DEVELOPMENT RESEARCH) for support for the LIFE Pilot Study, a population-based prospective study of pregnancy outcome in Medchal Mandal, Telangana.
Joseph M. Zmuda, PhD. Dr. Zmuda is an Associate Professor in the Department of Epidemiology at the University of Pittsburgh. He has extensive experience in the conduct and direction of epidemiological studies, particularly those focusing on osteoporosis and body composition. He will contribute to all aspects of the study including scientific direction and data analysis. He is the Principal Investigator of the Tobago Bone Health and Tobago Family Health Studies.