13Minimally Invasive and Innovative Methods for Biomeasure Collection in Population-Based Research

Lindau ST, McDade TW.

Publication Details

A new laboratory for health research has emerged at the intersection of the social and biomedical sciences. Sociological, demographic, and economic inquiries that have traditionally relied on self-reported health data are increasingly complemented by objective physical measures at the individual level. Biomedical investigations constrained by biases derived from clinic-based samples can now pursue questions about health disparities between social groups and about mechanisms linking social conditions to health and disease. Data from large probability samples can also provide valuable reference data for clinical diagnosis. Broad advances in information and biomedical technology, combined with emphasis on interdisciplinary research from the National Institutes of Health (2005), the National Academy of Sciences (2004), and others, have given momentum to new approaches to primary collection of individual-level health data that span subjective and objective social, health, and biophysiological domains. Hybridization of gold standard social science methodologies with minimally invasive techniques for biophysiological data collection in the home or in vivo defines a new frontier for health research.

In large part, these advances derive from rich traditions of field-based research that have valued the integration of multilevel data toward an understanding of human health and development. In the last several years, anthropometric measures (e.g., height, weight, waist and hip circumference) have replaced self-report or subjective estimates in many population-based studies and have proven highly clinically relevant. Similarly, clinical measures, such as blood pressure sphygmomanometry, spirometry, and bone densitometry, have been successfully incorporated into epidemiological and other population-based health research. Investigators seeking to incorporate biophysiological measures must regularly choose between tried and true measures with established validity, reliability, and predictive power and experimental or cutting-edge measures, such as those that may have unknown clinical utility or are newly adapted to home-based collection procedures.

For this reason, in our review of innovative biophysiological methods suitable for population-based research, we include (1) methods with a track record of successful implementation in population-based research, (2) established clinical methods amenable to use in population settings, and (3) emerging and experimental methods with promise for future population research. This review is oriented toward experienced population researchers with interest in health but with limited experience in the collection of objective measures of biological function. We emphasize procedures and rationale for collection of biological measures that can be reasonably implemented in field settings and that can be meaningfully integrated with survey research.

ISSUES IN THE APPLICATION OF MINIMALLY INVASIVE METHODS

Biological measures collected in the population setting can include direct measures of physical or physiological characteristics (e.g., hip circumference, blood pressure), functional testing (e.g., cognitive function, balance, grip strength), or collection of specimens that require laboratory processing in order to generate analyzable data. Such data may also be generated via experimental design (e.g., neuropsychiatric or olfactory testing). In traditional survey research, such constructs are approximated using self-report or subjective assessment by the study subject or the data collector (or both).

Translation of clinical or other laboratory methods for data and specimen collection to the population setting can occur by replication or adaptation. For example, investigators may choose to replicate the clinical encounter by sending a clinician, nurse, or phlebotomist to the home to conduct a physical examination or venipuncture for blood, or to bring participants into a mobile clinic close to where they live or work. Alternatively, adaptation of clinical or experimental laboratory methods using minimally invasive strategies and nonmedically trained interview personnel may enhance the feasibility of data collection and prove more cost-effective (Rockett, Buck, Lynch, and Perreault, 2004). Furthermore, the thrust for minimal invasiveness in population-based health research encourages technological innovation (e.g., development of easily portable medical equipment, adaptation of venous blood assays for use with dried blood spots) that may contribute to improvements in clinical medical services, particularly in remote and resource-poor areas. Data from the largest ongoing population-based health study in the United States, the National Health and Nutrition Examination Survey (NHANES), uses a replicative approach (e.g., state-of-the-art mobile clinics) and provides a wealth of gold standard measures against which adapted methods can be benchmarked.

As with any survey measure, several key considerations should guide decisions regarding implementation and application of biomeasures in population research. Test performance characteristics, such as reliability, validity, sensitivity and specificity, in combination with information about the expected distribution of the measure of interest in the population, require close attention. Issues particularly relevant to biological measures include the relationship of the instrument and measure to the clinical or laboratory gold standard, focused training of data collectors who may have limited experience with these methods, and quality control at the levels of data collection, transportation, and sample analysis. Changes in the availability of instrumentation and laboratory reagents may pose challenges for comparability across time and studies. Knowledge about the physiological and biological mechanisms pertinent to the system of interest, as well as variations in these across populations, is critical; this informs the sample design and size, timing, interpretation, consideration of relevant confounders, and the full range of environmental and contextual factors that may influence the measure and the process of measurement.

In the context of population-based research, several criteria must be met in order to achieve the goals of minimal invasiveness (Box 13-1). Minimally invasive methods aim to minimize burden to and maximize the safety of research subjects and data collectors and to contain research costs (York, Mahay, and Lindau, 2004; Mack, 2001).

Box Icon

BOX 13-1

Principles of Minimal Invasiveness in Population-Based Biomeasure Collection. Compelling rationale: high value to individual health, population health, or scientific discovery. In-home collection is feasible.

BIOMEASURES AND TECHNOLOGIES WITH ESTABLISHED USE IN THE POPULATION SETTING

Anthropometrics

External measures of physical dimensions can be used to assess body size and composition as indicators of energy balance and nutritional history (Gibson, 2005; World Health Organization, 1995). Anthropometric measures can be performed quickly with portable equipment at minimal cost and therefore represent a set of objective health measures with low barriers to implementation. The availability of standardized methods and reference data improve the precision, reliability, and comparability of these measures (Lohman, Roche, and Martorell, 1988).

Commonly obtained anthropometric measures include height and weight, as well as circumferences and skinfold thicknesses taken from various locations on the body (Lohman et al., 1988). Raw measures are often converted to indexes or compared with age- and sex-specific reference values. For children, particularly in low-income settings, standardized scores for height-for-age, weight-for-age, and weight-for-height have long been used to identify short- and long-term growth faltering that increases risk for subsequent morbidity and mortality (World Health Organization, 1995). With growing awareness of an impending epidemic of overweight/obesity—both in the United States and internationally— body mass index (BMI, also called Quetelet's index; weight in kg/height in m2) is frequently used as a tool for assessing weight relative to height in both children and adults.

However, BMI cannot differentiate lean tissue weight from weight due to body fat, nor does it reveal the pattern of fat distribution (e.g., central versus peripheral) that may be more predictive of disease risk. Waist-to-hip ratio, waist circumference, and strategically placed skinfold measurements provide more direct indicators of the quantity and distribution of fat and have therefore been implemented in a large number of epidemiological studies (Gibson, 2005). Better estimates of body fat also allow more accurate determinations of lean mass, which may have implications for bone loss and glucose metabolism. Recently leg length in adulthood has received attention as a potential indicator of nutritional quality in early childhood, when leg growth is most rapid and may be compromised by adverse environments (Wadsworth, Hardy, Paul, Marshall, and Cole, 2002).

More precise estimates of fat-free mass, fat mass, and relative body fat can be obtained through biological impedance analysis (BIA), using portable instruments that measure the impedance of a small electrical current passed through the body (National Institutes of Health, 1996). Computerized tomography, magnetic resonance imaging, and dual energy X-ray absorptiometry (DEXA) provide highly precise measures of body composition in clinical and laboratory settings, but they are too costly and cumbersome for field settings. However, relatively portable DEXA and ultrasound densitometry instruments have been successfully used in community settings to measure peripheral bone mass as a predictor of fracture risk (Andersen, Boeskov, Holm, and Laurberg, 2004; Wear and Garra, 1998).

Grip Strength

Several population-based studies, particularly studies on aging, have incorporated measures of hand grip strength as a biomarker of general muscle strength. Grip strength offers a relatively simple, minimally invasive measure of motor performance that has been shown to correlate with health status and a variety of health outcomes, including general physical function, bone density, mobility, and long-term mortality (Schaubert and Bohannon, 2005; Bohannon, 2001). Early work using grip strength in a French population study demonstrated progressive loss in strength with age (Clement, 1974).

Handheld dynamometry has been used as a research tool since 1916. In a thorough review of the technology, four classes of instruments commonly used for measuring grip strength in the clinical setting are described: (1) hydraulic dynamometers, (2) sphygmomanometers, (3) the vigorimeter (manometer with tubing and rubber ball), and (4) computerized dynamometry (Shechtman, Gestewitz, and Kimble, 2005). Hydraulic dynamometers, adapted from the gold standard Jamar™ dynamometer developed in 1954, have been the most widely used instrument in the population setting. This instrument uses a hydraulic mechanism to register static grip strength in pounds (kilograms) of force and is manufactured in portable, handheld models. Although protocols vary, testing typically involves two or three repeated trials of hand contraction separated by periods of rest with the subject in a comfortable seated position (for clinical protocol detail, see Shechtman et al., 2005).

Related measures that have been successfully used in population studies include lower extremity dynamometry, body weight, body mass index, chair stand, and timed-up-and-go (Schaubert and Bohannon, 2005). Computer-based, portable dynamometry for hand grip, pinch strength, and lower extremity strength may significantly enhance measurement and ease of integration with survey data collected in population studies.

Accelerometry

Physical activity is a central part of energy balance, but it is difficult to measure through self-report methods. Accelerometry provides objective measures of the frequency, intensity, and duration of physical activity in everyday settings (Crouter, Clowers, and Bassett, 2006; Chen and Bassett, 2005; Welk, Schaben, and Morrow, 2004). Several watch-sized monitors are commercially available and are worn on the wrist, ankle, or waist. These monitors record acceleration of the body in one, two, or three dimensions and collect data for hours, days, or even weeks at a time. Some units have event markers, as well as light and temperature sensors. Data on acceleration events per unit time are downloaded and analyzed to provide estimates of physical activity and energy expenditure. At this point, data reduction algorithms are not standardized, and different approaches have significant implications for outcome variables (Masse et al., 2005).

Accelerometry has been widely used in the exercise sciences and is increasingly applied to research on obesity and sleep (Treuth, Hou, Young, and Maynard, 2005; Ancoli-Israel et al., 2003; Yngve, Sjöström, and Ekelund, 2002). An accelerometry module was added to NHANES in 2003. Heart rate monitoring has also been successfully used in field settings to measure physical activity and energy expenditure (Wareham, Hennings, Prentice, and Day, 1997; Leonard, Katzmarzyk, Stephen, and Ross, 1995), and improved estimates may be possible with the integration of accelerometry and heart rate data (Strath, Brage, and Ekelund, 2005).

Dried Blood Spots

Population-based health research often seeks to define the reciprocal effects of health and sociodemographic factors. Until recently, the measurement of biological measures in blood specimens was the exclusive domain of clinical or laboratory research. Many key biomarkers of health and physiological function are accessible only through serum or plasma, but venipuncture is a relatively invasive procedure that has served as an impediment to the application of biomeasures to population-level research. Dried blood spots—drops of capillary whole blood collected on filter paper following a simple prick of the finger—represent a viable alternative to venipuncture and have recently been incorporated into a number of population-based studies. Table 13-1 summarizes the range of analytes currently being measured in blood spots among these studies. For additional information, see McDade, Williams, and Snodgrass (2007). This follows on the success of previous applications in remote settings internationally, including lowland Bolivia, Samoa, Kenya, Papua New Guinea, and Nepal (McDade et al., 2005; Shell-Duncan and McDade, 2004; Panter-Brick, Lunn, Baker, and Todd, 2001; McDade, Stallings, and Worthman, 2000; Worthman and Stallings, 1997).

TABLE 13-1. Recent Applications of Dried Blood Spots (DBS) in Large Population-Based Studies.

TABLE 13-1

Recent Applications of Dried Blood Spots (DBS) in Large Population-Based Studies.

Sample collection is relatively straightforward, and can be implemented by nonmedical interviewers: (1) the participant's finger is pricked using a sterile, single-use disposable lancet; (2) up to five drops of blood are spotted onto filter paper; (3) samples are allowed to dry (four hours to overnight); and (4) they are shipped via express or standard mail to the laboratory for freezer storage (most analytes are stable in dried blood spots at normal room temperatures for at least two weeks). A small disc of dried whole blood is punched from the filter paper blood spot and is placed in solution to create a sample of reconstituted blood, analyzable in a similar manner as a serum or plasma sample. Since these filter papers were originally developed to facilitate the collection of blood samples from neonates as part of an ongoing national screening program, they are certified to performance standards for sample absorption and lot-to-lot consistency (Mei, Alexander, Adam, and Hannon, 2001).

Protocols for over 100 analytes have been validated, including important indicators of endocrine, immune, reproductive, and metabolic function, as well as measures of nutritional status and infectious disease (McDade et al., 2007). Many of these biomarkers have been applied clinically and may be used in survey research to determine risk for the development of disease or to gain insight into the impact of psychosocial or behavioral contexts across multiple physiological systems. Recent innovations in immunoassay technology now make it possible to simultaneously quantify multiple analytes in one sample, rather than measuring one analyte at a time (Bellisario, Colinas, and Pass, 2000).

Advantages of dried blood spots include the minimally invasive sample collection procedure, simplified field logistics associated with sample processing, transport, and storage, and long-term stability under freezer storage that allows for future analyses as new biomarkers of interest, such as genetic markers, emerge (McDade et al., 2007). Disadvantages derive primarily from the fact that biomarker measurement in serum or plasma represents the gold standard in clinical assessment. Protocols must therefore be validated specifically for use with dried blood spots, and results may not be directly comparable with serum or plasma methods. In addition, the relatively small quantity of sample collected with blood spots may be an insurmountable limitation for some analytes that require large volumes of blood.

Urine

Among biospecimens amenable to home collection, urine provides a relatively simple platform for a very wide array of analyses. These include measures of renal, neuroendocrine, and sex hormone function, urine chemistry and cytology, nutritional measures, human chorionic gonadotropin (pregnancy hormone), microbes including sexually transmitted agents (e.g., chlamydia, N. gonorrhea, trichomonas, HIV) uropathogens, toxic substances, drugs, and drug metabolites (Rockett et al., 2004). Assays for the measurement of reproductive hormones or neuroendocrine metabolites commonly require collection of multiple urine voids over time (e.g., overnight, 12- or 24-hour periods, or daily) and sometimes involve food restriction, but most other assays can be performed on a single urine specimen. For some assays, and with younger participants, a first morning specimen can approximate an 8-12 hour multiple void collection. Measurement of urinary creatinine, a metabolic correlate of muscle mass that is normally found in relatively constant concentrations in urine, can be used to adjust for variability in urinary volume and concentration (Garde, Hansen, Kristiansen, and Knudsen, 2004; Naranayan and Appleton, 1980).

In addition to data obtained via laboratory processing, physical characteristics of urine, such as color, odor and temperature, can be useful. Urine temperature measured via an adhesive thermometer strip applied to the specimen cup can provide a close approximation of core body temperature. Decisions about specimen collection media depend on the volume of urine to be collected, the desired assays, and transportation issues.

In most cases, urine is collected in plastic specimen cups or jugs. However, innovative collection methods include filter paper, diapers, and commode collection pans. Although filter paper collection is limited by the paucity of validated assays, further development could substantially improve ease of transportation and storage. For most assays, urine must either be refrigerated or frozen within two hours (Simerville, Maxted, and Pahira, 2005) of collection and therefore requires cold storage or packaging. This method has been widely used and found acceptable in population studies with younger and older samples, men and women, and in a variety of cultural settings (Auerswald, Sugano, Ellen, and Klausner, 2006; Zheng et al., 2005; Serlin et al., 2002; Wawer et al., 1998). Cell-free genetic information (DNA molecules) may also be obtained and amplified from urine specimens (Botezatu et al., 2000).

Saliva

For many biomarkers, saliva is an attractive alternative to blood sampling since collection is noninvasive and can be successfully performed by participants in their homes or as they go about their normal daily routines. Furthermore, many assays that can be collected via blood can also be obtained from saliva. Repeat sampling is possible, and saliva can be collected from infants and children with minimal difficulty. Most analytes are stable at room temperature for up to a week—much longer for some analytes and collection devices—and saliva samples can therefore be stored and shipped without refrigeration for limited periods of time (Hofman, 2001). For these reasons, biobehavioral research has a track record of success with saliva sampling, both in experimental and naturalistic settings (Nepomnaschy et al., 2006; Gunnar and Donzella, 2002; Beall et al., 1992).

Assays for physiological indicators of stress, immune function and infectious disease, reproductive function, and drug use have been validated for use with saliva (Hofman, 2001; Granger, Schwartz, Booth, and Arentz, 1999; Nishanian, Aziz, Chung, Detels, and Fahey, 1998; Kirschbaum and Hellhammer, 1994; Ellison, 1988). In most cases, salivary measures are of value only if they reflect circulating concentrations in serum. This may be an insurmountable obstacle for some analytes. For others (e.g., steroid hormones), concentrations in saliva are free of binding proteins and may provide a better estimate of the active fraction in circulation (Vining, McGinley, and Symons, 1983).

Despite the noninvasive nature of saliva sampling, there are a number of important issues in the collection and processing of saliva that may significantly affect assay results. For example, concentrations of some analytes are affected by salivary flow rate, as well as contamination of saliva with blood or food (Kivlighan et al., 2004; Kugler, Hess, and Haake, 1992). The use of oral stimulants to promote saliva production and the absorption of saliva into cotton rolls to facilitate sample collection have been shown to modify assay results for some, but not all, analytes (Shirtcliff, Granger, Schwartz, and Curran, 2001; Schwartz, Granger, Susman, Gunnar, and Laird, 1998). The composition of the containers (e.g., glass, polystyrene) in which saliva is collected and stored can also affect some results and should be evaluated for each analyte (Ellison, 1988). These issues, as well as the application of different laboratory protocols, can lead to difficulties in interpretation and comparison across studies (Hofman, 2001).

Currently, salivary cortisol is frequently measured in naturalistic settings as a biomarker of stress, reflecting activation of the hypothalamic-pituitary-adrenal axis (Adam, 2006; Cohen et al., 2006; Kirschbaum and Hellhammer, 1994). Normal diurnal rhythms in cortisol production provide the opportunity to investigate concentrations at different times of day, patterns of change across the day, and overall levels of cortisol exposure. However, this variation poses significant challenges to measurement, with little consensus on sampling protocols beyond recognition of the importance of collecting multiple samples per day, preferably across multiple days. The timing of sampling is critical, particularly in the morning, and some studies have used timers or tracking devices to ensure compliance with collection protocols (Broderick, Arnold, Kudielka, and Kirschbaum, 2004).

TRANSLATION OF ESTABLISHED CLINICAL TECHNOLOGIES TO THE POPULATION SETTING

Ambulatory Electrocardiogram

Holter monitors provide the possibility of measuring heart rate variability continuously as participants go about their normal daily activities. A compact monitor is worn on the waist or over the shoulder, and electrodes attached to the chest record heart rate activity for 24 to 72 hours. Analysis of electrocardiogram data can be used to assess cardiac arrhythmias and vagal tone, both of which have been analyzed in relation to psychosocial factors and cardiovascular risk (Cacioppo, Tassinary, and Berntson, 2000; Kawachi, Sparrow, Vokonas, and Weiss, 1995). Holter monitoring is widely used clinically and has considerable potential for population-based research.

Spirometry

Pulmonary function testing is a mainstay of pulmonary medicine and plays an important role in the monitoring of such common diseases as asthma and obstructive pulmonary diseases. Spirometry has been used in several population studies, providing measures of lung volume (e.g., forced expiratory volume in one second or FEV1) and expiratory flow (e.g., peak expiratory flow or PEF), as well as estimates of lung capacity (e.g., forced vital capacity or FVC).

More recently, spirometry has been incorporated into home-based studies as an indicator of vitality or disability and has been found to be a useful predictor of functional status and decline in the elderly. Data from large, population studies demonstrate that reduced lung function as measured by FEV1 is associated with systemic inflammation (e.g., elevated C-reactive protein) and cardiovascular mortality independent of smoking (Sin, Wu, and Man, 2005), and it may be an independent predictor of long-term mortality (Schunemann, Dorn, Grant, Winkelstein, and Trevisan, 2000). A variety of portable spirometry devices are available, including handheld peak flow meters and computer-based devices (most clinical centers in developed nations use computerized spirometry). Interpretation of spirometry data for diagnostic purposes requires comparison with an appropriate reference group. An excellent review provides spirometry testing and interpretation standards as well as an overview of available equipment (Ruppel, 1997). Data from NHANES III provide clinic-based spirometry reference values for whites, African Americans, and Mexican Americans ages 8-80 (Hankinson, Odencrantz, and Fedan, 1999).

Evaluation of portable spirometers against laboratory spirometry shows acceptable agreement (Ezzahir, Leske, Peiffer, and Trang, 2005; Korhonen, Remes, Kannisto, and Korppi, 2005; Mortimer, Fallot, Balmes, and Tager, 2003; Koyama, Nishimura, Ikeda, Tsukino, and Izumi, 1998), but poor intermodel agreement (Koyama et al., 1998). This implies that longitudinal studies using peak flow meters should avoid changing meter models from one wave to another and highlights the importance of working with an established and reliable proprietor. Use of spirometry or peak flow meters in population research, particularly with nonmedically trained interviewers, requires careful training and a very detailed protocol. Similar to Holter monitoring, development of portable spirometers that have the capacity for longitudinal data storage and phone or computer line transmission (i.e., telemetry) may facilitate longitudinal home-based data collection (Giner and Casan, 2004; Wagner et al., 1999).

Hearing

Technological advances have significantly facilitated the transfer of audiometrics from the clinical to the population setting; in the near future, handheld and laptop-based platforms for hearing testing are likely to replace gold standard audiometry equipment even in clinical settings. For population studies, integration of audiometry software with laptop-based questionnaires may significantly enhance ease of implementation. Hearing testing has been widely used in population studies, particularly with older adults (e.g., NHANES, Sin et al., 2005) and the Leiden, Netherlands, 85+ Study (Gussekloo, de Craen, Oduber, van Boxtel, and Westendorp, 2005). Self-report is a poor indicator of hearing function (Newman, 1990).

Several minimally invasive instruments are currently available for hearing testing. The most widely used is the portable audiometer, a handheld device that performs physiological audiometry. A hybrid device, the audioscope, combines audiometry with an otoscope (allowing for direct inspection of the ear canal and tympanic membrane). Portable audiometry in the frequency ranges of human speech (between 500 and 4,000 Hz at 25-40 dB) demonstrates excellent sensitivity against the gold standard (pure tone audiometry with sound booth isolation) and good specificity, but because it provides a physiological rather than a functional test, it may detect individuals with asymptomatic hearing loss. In contrast, it may fail to detect individuals with functional hearing impairment. These are appropriate for home use and can be handled by lay personnel.

Currently, the high cost of portable audiometry has limited its application in population studies. The Hearing Handicap Inventory for the Elderly-Screening Version (HHIE-S) offers a low-cost, widely used alternative to objective physiological measurement of hearing. This 10-item, 2-5 minute test screens for functional hearing, with scores on a 0-40 point scale indicating a probability of hearing impairment. It has been widely used in population studies with acceptable performance compared with audiometry in detecting hearing loss. Older measures used to screen for hearing loss aim to detect threshold sensitivity to whispered voice, the sound of the examiner's fingers rubbing together, or vibratory sensation with a tuning fork. Concerns about the subjectivity and particularly reliability of these measures limit their use (Pirozzo, Papinczak, and Glasziou, 2003).

Vision

Similar to hearing loss, ocular disorders are strongly associated with psychosocial impairment (Burmedi, Becker, Heyl, Wahl, and Himmelsbach, 2002), and have been related to increase in mortality (Knudtson, Klein, and Klein, 2006). Protocols appropriate for home-based vision testing, particularly acuity assessment, can be informed to some degree by clinical procedures and large-scale clinic-based studies that use population samples, such as the Beaver Dam Eye Study (Klein, Klein, Linton, and De Mets, 1991), the Baltimore Eye Survey (Tielsch, Sommer, Witt, Katz, and Royall, 1990), the Blue Mountains Eye Study (Attebo, Mitchell, and Smith, 1996), and the Salisbury Eye Evaluation Study (Muñoz et al., 2000). NHANES has also performed vision testing with population samples in a mobile clinic setting (Vitale, Cotch, and Sperduto, 2006). Together, these studies provide useful population prevalence estimates of vision impairment and blindness (see Table 2 in Xu et al., 2006).

However, these studies typically bring individuals from a population sample into a clinical examination setting. Home-based acuity testing is limited in part by the size and rigidity of eye charts, the need for standardized lighting, and, in small residential spaces, the chart distance requirements. An excellent review of visual acuity assessment summarizes the most widely used charts and scales for visual acuity testing of adults and children, such as the Snellen eye chart, the Early Treatment Diabetic Retinopathy Study Charts (ETDRS), and symbol charts that do not require English language or literacy skills (Kniestedt and Stamper, 2003). Studies in developing countries have perhaps made greatest use of field-based visual acuity testing (Gouthaman et al., 2005; Amansakhatov, Volokhovskaya, Afanasyeva, and Limburg, 2002), using adaptations of the Snellen tumbling “E” chart or the ETDRS chart in ambient indoor lighting, sunlight, or portable lighting. Similar to developments with auditory testing, researchers are investigating the performance of computerized acuity testing (Rosser, Murdoch, Fitzke, and Laidlaw, 2003), although this has not yet been widely implemented. Also on the horizon, fundus photography and other imaging instruments that can be used without retinal dilation (Wang, Tielsch, Ford, Quigley, and Whelton, 1998) may provide innovative opportunities for population-based research. Cost and ease of application by nonmedical personnel will determine the usefulness of these technologies in the field setting.

Point-of-Care Devices

Recent technological advances have led to the development of small, portable “point-of-care” devices that analyze clinically important biomarkers in real time (Glazer, 2006). As with blood spot sampling, a sterile lancet is used to stimulate the flow of capillary whole blood, and a drop of blood is placed into a cartridge or cuvette, which is then inserted into the instrument. Results are available onsite seconds or minutes later. The HemoCue™ instrument for analysis of hemoglobin has been widely used in international and domestic settings, and other portable devices are currently available, such as those that measure glucose, HbA1c, CRP, lipids, blood chemistry, or liver function in a single drop of blood. Devices vary in weight, ease of setup, whether they can operate on batteries, and the conditions under which cartridges must be stored prior to use. A single finger prick can provide capillary whole blood for onsite analysis, as well as for collection on filter paper as dried blood spots. By combining these procedures, results can be shared with participants, while blood spots can be assayed in the lab for a broader range of measures. In some cases, this may provide valuable health screening services and act as an incentive for research participants.

TRANSLATION OF EMERGING AND EXPERIMENTAL METHODS TO THE POPULATION SETTING

Given rapidly growing interest in the integration of biomeasures into population-based data collection efforts, acceleration in the translation of new technology from clinical and experimental laboratory research is expected. As an example, the National Social Life, Health, and Aging Projects (NSHAP) study recently completed collection of a broad panel of sensory function data using lay interviewers in the home setting with excellent cooperation from field staff and respondents. This required adaptation of experimental methods used to quantify olfactory and gustatory function in the laboratory setting as well as use of a simple and affordable clinical measure of tactile sensation.

Tactile Sensation

Measures of tactile sensation have not yet been widely implemented in broad population studies. Aside from use by hand surgeons, therapists, and neurologists to quantify neurological deficit and recovery, for example before and after hand surgery, population studies are limited to military personnel or workers using vibratory equipment (Wild et al., 2001) or method validation studies (Kaneko, Asai, and Kanda, 2005). NSHAP, a study of the interactions between social and biological factors at older ages, incorporates tactile sensation as part of a global evaluation of sensory function. Variations in touch sensibility may indicate microvascular disease, as seen in diabetes, or they may correlate with social characteristics, such as occupation or social contact with others. Cognitive function may also influence touch sensibility measures (Lundborg and Rosen, 2004). In a study of volunteers, thresholds for digital pressure perception appeared to increase with age (Kaneko et al., 2005).

Sensation to touch, or hand sensibility, has long been estimated in the clinical setting using the two-point discrimination test (2PD), described originally by Weber in 1835 (Lundborg and Rosen, 2004). This test measures the distance (in millimeters) between two points necessary for the individual to feel two distinct contacts, indicating peripheral innervation density. 2PD instruments range from a simple paper clip or compass (aesthesiometer, about $65 U.S.) to a multisided handheld instrument with graded intraprong distances (e.g., Dellon's Disk-Criminator™, about $100 U.S.) to pressure-specifying devices with force transducers in order to standardize application pressure. Despite concerns regarding standardization of 2PD equipment and protocols, particularly with regard to application of pressure with the prongs, 2PD has been demonstrated to be a valid measure of chronic nerve compromise (Dellon and Keller, 1997). Semmes-Weinstein nylon filaments provide greater standardization in sensation and pressure perception testing (Mayfield and Sugarman, 2000) but are relatively expensive for population use. Computer-assisted sensorimotor technologies are also available and may offer better performance, but they have not yet been adapted for nonclinical use (Dellon and Keller, 1997).

Taste

Gustatory function plays an important role in nutrition and quality of life and serves as a defense against ingestion of noxious or toxic substances. Because social interactions and cultural traditions frequently involve eating, impairment of gustatory sensibility can be associated with social alienation or withdrawal. The vast majority of gustatory function testing occurs in the clinical or laboratory settings, with important applications to diagnosis and prognosis of common otolaryngological and neurological disorders. Commonly used medications can interfere with gustatory function. Aging can result in diminished sensitivity to some tastes, salty and sweet for example, and therefore increased intake of foods that can have negative health consequences (Schiffman, 1997). Oral mucosal changes in postmenopausal women may contribute to changes in gustatory function with age (Delilbasi, Cehiz, Akal, and Yilmaz, 2003).

Work led largely by German researchers has resulted in advancement of minimally invasive, easily portable, and well-performing methods for gustatory testing appropriate for population use. The latest of these innovations involves use of tastant-impregnated paper strips (sour, sweet, salty, bitter) in varying concentrations for evaluation of taste identification ability and threshold sensibility. The strips are designed so that both sides of the tongue can be tested separately. Long shelf life, ease of administration, and a relatively brief protocol offer major advantages over liquid-based drop tests commonly used for clinical purposes (Mueller et al., 2003). NSHAP has just completed olfactory testing using this method with a national U.S. probability sample of more than 3,000 men and women ages 57-85 with very high cooperation rates. Other technologies for gustatory testing that could be used in the home include taste disks and edible taste wafers. As opposed to regional testing accomplished with the taste strips, these measures provide whole mouth tests of gustatory function, perhaps a truer measure of everyday taste experiences (Ahne, Erras, Hummel, and Kobal, 2000). Of course, everyday taste experience typically involves complex combinations of tastes and aromas. Interdependence between taste and olfactory function limits the value of assessing one without the other (Mueller et al., 2003).

Olfaction

Over the last several years, a growing body of evidence linking olfactory function to cognitive decline at older ages has prompted both public and research interest in this area and has motivated development of portable, minimally invasive, efficient olfactory function tests. Decline in olfactory function appears to occur with age (50 percent between ages 65 and 80 suffer significant loss of function—Frank, Dulay, and Gesteland, 2003) and some common medical illnesses and medication use, and it is closely related to taste sensibility. Compromised olfaction presents a risk for injury or other hazardous events, such as inability to detect smoke or other noxious fumes and consumption of spoiled food (Santos, Reiter, DiNardo, and Costanzo, 2004). Olfactory function testing shares common principles with psychophysical testing of gustatory and other chemosensory abilities; odorants are presented and the subject is assessed on the ability to detect, identify, and discriminate these (Doty, 2006). Although most authors agree that no gold standard olfactory assessment test exists, many are compared with the widely used 40-item University of Pennsylvania Smell Identification Test (UPSIT) (Doty, Shaman, and Dann, 1984), a comprehensive, self-administered, odor Identification test using a scratch-and-sniff technique. Although probably too time-consuming for most population studies, this measure has been used in over 50,000 individuals and is validated in several languages (Doty, 2006).

A recent review article (Doty, 2006) describes the broad range of olfactory function measures available and provides a concise primer on the relative benefits and drawbacks of each. Shortened versions of the UPSIT have been successfully implemented in some clinical settings. In addition to the scratch-and-sniff technology, several other modalities offer options for population studies. These include “Sniffin' Sticks,” which use a penlike odor device (Mueller and Renner, 2006; Hummel, Konnerth, Rosenheim, and Kobal, 2001; Kobal et al., 2000) and the odor stick Identification test from Japan (Hashimoto et al., 2004). A laptop-based device is used for the sniff magnitude test, which assesses olfactory ability by comparing the nature of a person's sniff in response to air versus sniff with odors. Although used primarily in the clinical research setting, the laptop-based operation and data capture offer unique advantages over other olfactory test methods. The NSHAP study protocol for olfactory function testing in a large probability sample of older adults is an adaptation of the short Sniffin' Sticks olfactory function screening method (Mueller and Renner, 2006) and takes about 3-5 minutes to administer with very high cooperation rates (> 90 percent).

Vaginal Self-Sampling

Vaginal self-sampling provides population and clinical researchers a minimially invasive method for obtaining data historically restricted to the clinical setting in which a gynecologic pelvic examination could be performed. In addition to microbial pathogen data, quantification of the normal vaginal flora and mucosal inflammation provide data points of relevance to health, sexual behavior and function, and systemic hormonal and inflammatory processes. In comparison to the methodologies summarized here, vaginal self-sampling imposes relatively high respondent burden, albeit much less so than a gynecological examination. The implementation of this method, which requires a respondent to self-collect vaginal material in a private setting by inserting and rotating one or more small, sterile cotton- or Dacron™-tipped swabs, a small cytobrush, or a tampon in the vagina, derives primarily from experience in remote field settings where clinical pelvic examination is infeasible. Recent introduction of flexible menstrual collection devices provides another method for self-sampling to obtain cervicovaginal secretions (Boskey, Moench, Hees, and Cone, 2003) and biomeasures of menstruation (Koks, Dunselman, de Goeij, Arends, and Evers, 1997).

Once the samples are obtained, they are placed into transport media appropriate to the assays of interest and typically must be frozen and delivered to a laboratory for analysis. Established clinical protocols for microbial testing are appropriate for specimens collected in the home; the NSHAP study is also developing protocols for home-based vaginal sampling appropriate for cytological analysis. The vaginal self-swabbing method has demonstrated acceptability to study participants in a variety of settings (e.g., Bradshaw, Pierce, Tabrizi, Fairley, and Garland, 2005; Chernesky et al., 2005; Nelson, Bellamy, Gray, and Nachamkin, 2003; Serlin et al., 2002) and has performed favorably in comparison to urinary and clinical pelvic examination protocols for testing of sexually transmitted infections (e.g., Harper, Noll, Belloni, and Cole, 2002; Knox et al., 2002).

Vaginal self-sampling requires careful selection and training of field staff to maximize both respondent and data collector comfort with and understanding of the rationale and steps for the sampling procedures. Cervical self-sampling can also be accomplished using similar techniques and can approximate Papanicalou smear findings. However, interpretation of assays, designed to detect dysplastic or malignant conditions, requires expert or expertly supervised personnel. Furthermore, anticipatory guidance for research subjects must include clear information about the physical effects of self-sampling (e.g., transient irritation or a small amount of discharge or blood are not uncommon following sampling in older women) and whether the specimen will or will not be used for cancer screening. In almost all cases, implementation of vaginal sampling in population studies requires a professional results reporting and counseling mechanism, such as that offered by the American Social Health Association.

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) is a critical diagnostic tool that provides a window into the inner workings of the human body, but one that is not easily adapted to population research due to technical and logistical constraints. Brain imaging is emerging as a fundamental tool for social neuroscience inquiry that aims to locate and map the neurological pathways through which social stimuli may influence health and health outcomes. However, MRI systems contained in mobile trailers must be transported to centralized locations for community-based research. In addition, a portable MRI device has recently been developed that can provide images of the extremities, although, at a weight of approximately 100 pounds, it is still too large for household surveys. Additional innovations in MRI and functional MRI are likely to lead to more portable instrumentation in the near future.

ADJUNCT METHODS

Widely used by psychiatric and psychological researchers, experience sampling methods do not directly measure biological or physiological parameters, but instead serve as an adjunct to such measurements by providing documentation of real-time health-related information, feelings, symptoms, reflections, and thoughts or events pertinent to the individual psychosocial context, such as stress, mood, emotion, and well-being. These include paper-and-pencil diary, thought sampling (Hurlburt, 1997), and ecological momentary assessment (Stone and Shiffman, 1994) and are uniquely home- or field-based. However, most examples in the literature involve convenience, rather than probability, samples. These methods aim to reduce reporting bias caused by recall and the constraints of close-coded instruments used in traditional designs. Although the use of paper-and-pencil diaries for research dates to the 1940s (Bolger, Davis, and Rafaeli, 2003), thought sampling and experience sampling methods appear to have emerged nearly simultaneously in the mid-1970s (Hurlburt, 1997). Recently, Kahneman and colleagues reported on the Day Reconstruction Method, a hybrid of experience sampling methods and time-budget measurement (Kahneman, Krueger, Schkade, Schwarz, and Stone, 2004).

Vigorous debate in the recent literature about optimal diary methods suggests that no single method is superior for all study designs (Green, Rafaeli, Bolger, Shrout, and Reis, 2006; Broderick, Stone, Calvanese, Schwartz, and Turk, 2006; Bolger, Shrout, Green, Rafaeli, and Reis, 2006) and that these methods may, in some cases, be limited in their superiority to retrospective self-report (Takarangi, Garry, and Loftus, 2006). However, there is broad enthusiasm for advancement beyond paper-and-pencil methods toward augmentation with signaling devices (such as beepers, watch alarms, and phone calls) and for replacement of paper and pencil by electronic data collection using handheld devices, tablet personal computers, and electronic mail or web-based entries. The electronic devices offer the advantage of time- and date-stamping to corroborate subject compliance with the research protocol and to provide response-time data. Such devices may also enhance privacy, minimize the risk of data loss, allow for closer monitoring by researchers, and, combined with signaling, allow for dynamic flexibility in the intervals between entries. In addition to cost, some downsides of high-technology diary methods may include higher respondent burden due to disruptiveness, logistics of interacting with and transporting the equipment, or unfamiliarity with computer technology. A clinic-based study of patient compliance showed significantly higher compliance with an electronic versus paper-and-pencil diary (Stone, Shiffman, Schwartz, Broderick, and Hufford, 2003).

Rapid innovations in diary research methods include real-time electronic interaction with participants, voice recording and recognition technology for verbal entries, behavioral medicine technologies that integrate self-report of subjective mood, and cardiovascular and physical activity indices with ambulatory monitoring. One can imagine the combination of these innovative technologies with global satellite positioning; the value of the data versus potential infringements on subjects' privacy will have to be carefully weighed.

Medication use records provide another important adjunct to biomeasures, particularly in studies of aging. Self-report either by interview or self-administered questionnaire substantially limits the usefulness of such data. Direct observation of medication containers by in-home data collectors with immediate data entry is likely to improve data quality (Landry et al., 1988), but lack of unique identifiers for pharmaceuticals presents a major challenge with regard to coding and analysis.

CONCLUSION

Major advances in minimally invasive and portable biomedical technology and growing collaborations between social, biomedical, and life scientists, combined with state-of-the art survey technology, offer a tremendous opportunity for new kinds of health-related discovery. Many of the methods described here are innovative by virtue of bringing them into the field or home setting. Others implement novel inventions motivated by a desire to reach generalizable or remote samples. In the case of biological specimens, such as blood spots, saliva, vaginal samples, and urine, the power of the method is limited not by cooperation of the research participant, but by the availability and translation of suitable assays. The importance of high-quality, well-trained data collectors who embrace the rationale for biomeasure collection and can convey this to research participants cannot be underestimated. Innovations for population research that accomplish minimal invasiveness may facilitate cooperation in the clinical setting and diagnosis and treatment of disease in populations who otherwise would or could not access medical care.

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