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Problems and solutions in longitudinal research: from theory to practice.

Longitudinal studies provide the only method for directly studying the natural course of human growth and development and are therefore invaluable, both to public health and clinical medicine. However, longitudinal studies are accompanied by specific problems. The purpose of this final paper is to discuss in two separate sections some of the methodological, analytical and practical issues regarding the relevance of the findings reported. Examples of such problems and their solutions are described. Methodological issues discussed concern statistical conclusion validity, internal validity and construct validity of longitudinal studies. Practical issues discussed concern the design of longitudinal studies, the recruitment and retention of subjects, and the methods used. Finally, examples of the significance of longitudinal research outcomes to public health and clinical medicine are given.

Clinical Medicine↗

Statistical analysis of randomized trials in tobacco treatment: longitudinal designs with dichotomous outcome.

This article considers two important issues in the statistical treatment of data from tobacco-treatment clinical trials: (1) data analysis strategies for longitudinal studies and (2) treatment of missing data. With respect to data analysis strategies, methods are classified as 'time-naïve' or longitudinal. Time-naïve methods include tests of proportions and logistic regression. Longitudinal methods include Generalized Estimating Equations and Generalized Linear Mixed Models. It is concluded that, despite some advantages accruing to 'time-naïve' methods, in most situations, longitudinal methods are preferable. Longitudinal methods allow direct effects of the tests of time and the interaction of treatment with time, and allow model estimates based on all available data. The discussion of missing data strategies examines problems accruing to complete-case analysis, last observation carried forward, mean substitution approaches, and coding participants with missing data as using tobacco. Distinctions between different cases of missing data are reviewed. It is concluded that optimal missing data analysis strategies include a careful description of reasons for data being missing, along with use of either pattern mixture or selection modeling. A standardized method for reporting missing data is proposed. Reference and software programs for both data analysis strategies and handling of missing data are presented.

Humans↗

Homogeneity and heterogeneity in mild cognitive impairment and Alzheimer's disease: a cross-sectional and longitudinal study of 55 cases.

This study investigated cross-sectional and longitudinal neuropsychological data from 55 patients: 38 with Alzheimer's disease and 18 with mild cognitive impairment (MCI). The analyses were designed to investigate two issues: the relationship of MCI to Alzheimer's disease, and that of atypical to typical Alzheimer's disease. When longitudinal data were averaged across individual patients, a consistent staging of neuropsychological deficits emerged: the selective amnesia characteristic of the MCI phase was joined next by semantic and other linguistic impairments plus emerging difficulties with demanding visuospatial tasks. A two-stage statistical procedure was used to extract underlying factors that corresponded to the severity-governed decline in neuropsychological test scores and then to the consistent deviations away from this typical longitudinal profile; i.e. identifying patterns of atypical Alzheimer's disease. The severity-based factor accounted for nearly 60% of the variance in this MCI-Alzheimer's disease longitudinal and cross-sectional database. This suggests that there is a fairly high degree of homogeneity within this group of patients, and that most of their longitudinal progression can be predicted by dementia severity alone. There were also two main patterns of atypical variation corresponding to patients with exaggerated semantic or visuospatial deficits. Although such cases may mimic more focal lobar degenerative conditions, patients with atypical Alzheimer's disease have pronounced episodic memory impairments, suggesting amnesia as a critical diagnostic feature.

Alzheimer Disease↗

Muscle quality and age: cross-sectional and longitudinal comparisons.

We addressed whether muscle quality (force per unit muscle mass) changes with age in cross-sectional and longitudinal analyses from three groups from the Baltimore Longitudinal Study of Aging: (1) Isometric arm strength studied cross-sectionally in 617 subjects with muscle mass estimated by cross-sectional area (CSA) from arm circumference and by 24-hour urinary creatinine excretion (CREAT); (2) longitudinal study for 10 to 25 years in 412 men using the same measures as the first group; and (3) isometric knee extensor strength studied cross-sectionally in 675 subjects; muscle mass estimated by CREAT, CSA from thigh circumference, and leg nonosseous fat free mass (FFM) from dual energy x-ray absorptiometry. Muscle quality declined in both arm and leg with age in cross-sectional analyses using CSA and FFM, but not CREAT. No age-associated arm muscle quality declines were observed longitudinally using CREAT or CSA. The relationship between muscle quality and age is dependent on how muscle mass is estimated and on whether subjects are studied cross-sectionally or longitudinally. In addition, CREAT may measure a muscle property not accounted for by CSA or FFM.

Absorptiometry, Photon↗

Age-related slowing of digit symbol substitution revisited: what do longitudinal age changes reflect?

A previous investigation reported that cross-sectional age differences in Digit Symbol Substitution (DSS) test performance reflect declines in perceptual processing speed. Support for the tenability of the processing speed hypothesis requires examining whether longitudinal age-related change in DSS performance is largely mediated by changes in speed. The present study used data from the Victoria Longitudinal Study to examine patterns and predictors of longitudinal change in DSS for 512 older adults (M(age) = 68.37 years, SD = 7.43). On the basis of multilevel modeling, baseline DSS performance was poorer for older participants and men, with longitudinal declines more pronounced with increasing age and decreasing speed. In contrast to the present cross-sectional findings, statistical control of change trajectories in perceptual speed using the same data did not substantially attenuate age changes. These discrepancies suggest different sources of variance may underlie cross-sectional age differences and longitudinal age changes for DSS.

Aged↗

Impact of joint impairment on longitudinal disability in elderly persons.

Recent longitudinal data indicating that arthritis is a major contributor to disability in elderly persons are based on self-reported diagnostic information. This longitudinal study included baseline physical examinations of joints of 541 persons over age 60. Previous results from a cross-sectional multivariate model of disability in this sample found that joint impairment (and, its absence, arthritis pain) explained a significant proportion of variance in overall disability. We have retested this model using generalized estimation equations (GEE) analysis to estimate the effect of joint impairment and arthritis pain on baseline and Year 2 disability. Findings indicate that baseline joint impairment contributes substantially to longitudinal disability. If direct measures of baseline joint impairment are unavailable, concurrent self-reported arthritis pain also predicts longitudinal disability well. These findings indicate that longitudinal studies should monitor arthritis pain and that symptomatic arthritis is a risk factor for future disability.

Activities of Daily Living↗

Issues in the long-term evaluation of diet in longitudinal studies.

Longitudinal studies are very useful for studying diet/disease relationships. The fundamental components of a longitudinal study are that: 1) data are collected for two or more distinct time periods; 2) the subjects are the same or comparable from one time period to the next; and 3) data are compared between or among time periods in the analysis. A longitudinal study is often assumed to be synonymous with a cohort study, but there are at least four possible definitions for a longitudinal study. While focusing on cohort studies, the paper describes the nature of longitudinal studies, including a discussion of how the different definitions differ from a cohort study and a set of important assumptions necessary to cohort studies. It also highlights some of the major issues associated with such studies, including the selection of a dietary survey methodology; data collection issues in multicultural, multilingual societies; the importance of nutrient databases; measurement error and misclassification in nutrient intake and energy adjustment.

Cohort Studies↗

Atherosclerotic risk factors and renal function in the elderly: the role of hyperfibrinogenaemia and smoking. Results from the Italian Longitudinal Study on Ageing (ILSA).

BACKGROUND: We examined associations between cardiovascular diseases and risk factors with pathological levels of and significant changes in serum creatinine (SCr) in a large prevalence phase and longitudinal phase community-based sample of an elderly Italian population (ILSA Study) showing no clinical evidence of renal impairment. METHODS: The prevalence phase was performed on 2981 subjects, aged 65-84 years, who were negative for renal diseases, had available SCr values and had complete clinical information on their cardiovascular risk factors. Of these, 371 were considered 'healthy' since they were not affected by cardiovascular diseases or diabetes, whereas 2610 tested positive for cardiovascular diseases and were considered 'diseased'. The sex-specific 95th percentiles for SCr (cut-off points) were calculated in the healthy reference sample to define the upper limit for normal SCr values. The distribution and prevalence of diseased subjects having values over the cut-off point values were then estimated. Associations between values over the cut-off point levels and pathological or clinical conditions were analysed from the diseased sample. The longitudinal phase was carried out on 1906 subjects who had SCr values and sufficient clinical information for our investigation. The incidence of an increase of >26.5 micromol/l of SCr was evaluated in the longitudinal cohort. RESULTS: In healthy subjects, the 95th SCr percentiles (cut-off points) were 123.8 micromol/l in men and 97.2 micromol/l in women. In diseased subjects, the prevalence of SCr values over the cut-off point was 4.6% in men and 9.3% in women. In logistic regression analysis, independent variables that correlated with over the cut-off point SCr values were: age >75 years [odds ratio (OR) = 2.2; 95% confidence interval (CI) = 1.5-3.4], atherosclerosis of the lower limbs (OR = 2.0; 95% CI = 1.2-3.3), cerebrovascular disease (OR = 1.9; 95% CI = 1.2-3.3), angiotensin-converting enzyme (ACE) inhibitor medication (OR = 1.8; 95% CI = 1.2-2.8), fibrinogen values >3.5 g/l (OR = 1.2; 95% CI = 1.2-2.7) and diuretic treatment (OR = 1.6; 95% CI = 1.1-2.4). After a mean 3.6 years follow-up, multiple logistic regression analysis showed that risk factors for pathological loss of renal function (rise of SCr >26.5 micromol/l) were: current smokers >20 cigarettes/day (OR = 2.3; 95% CI = 1.0-5.3), fibrinogen values >3.5 g/l (OR = 2.2; 95% CI = 1.6-3.3), diabetes (OR = 1.8; 95% CI = 1.1-2.8), age >75 years (OR = 1.7; 95% CI = 1.2-2.4) and isolated systolic hypertension (OR = 1.6; 95% CI = 1.0-2.6). The loss of renal function examined during the longitudinal phase appeared to be independent of baseline SCr levels. CONCLUSION: The present prevalence and longitudinal studies show that age-associated decline in renal function in elderly subjects is associated with co-existing cardiovascular diseases and risk factors. These observations should be incorporated into clinical practice since some of the factors detrimental to kidney function, such as smoking, altered fibrinogen levels and elevated systolic blood pressure, can be prevented and/or modified when appropriate measures are taken.

Aged↗

Innervation of the rabbit lumbar intervertebral disc and posterior longitudinal ligament.

STUDY DESIGN: The present study sought to determine to what extent the lumbar intervertebral disc and posterior longitudinal ligament are innervated in the New Zealand white rabbit. The intent is to use this disc model in future neurophysiology studies. OBJECTIVE: To characterize the distribution of nerve fibers and endings in the lumbar intervertebral disc and posterior longitudinal ligament in an animal model. SUMMARY OF BACKGROUND DATA: The results of previous disc innervation reports are somewhat conflicting regarding the density and depth of innervation into the anulus. METHODS: A silver impregnation technique was used to analyze sections from lumbar intervertebral disc and posterior longitudinal ligament of the New Zealand white rabbit. RESULTS: Numerous fine profiles of nerve fibers were demonstrated in the lumbar disc anulus and posterior longitudinal ligament. In the disc, the nerves were limited to the superficial anulus and anular surface. The nerve axons typically were 1 to 3 microns in diameter and were found around the entire periphery of the disc. No encapsulated endings were seen within the anulus, while occasional encapsulated endings were seen on the anular surface and posterior longitudinal ligament. CONCLUSION: This study demonstrates an extensive distribution of small nerve fibers in the size range of C and A-delta fibers throughout the peripheral anulus and provides an illustration of this distribution. These findings support a role for the disc as a source of low back pain.

Animals↗

Morphologic limitations of posterior decompression by midsagittal splitting method for myelopathy caused by ossification of the posterior longitudinal ligament in the cervical spine.

STUDY DESIGN: This is a retrospective study of the morphologic limitations of posterior decompression for ossification of the posterior longitudinal ligament in the cervical spine. OBJECTIVES: To determine the morphologic limitations of the posterior approach in the management of ossification of the posterior longitudinal ligament. SUMMARY OF BACKGROUND DATA: Thirty-eight patients who underwent laminoplasty by midsagittal splitting for ossification of the posterior longitudinal ligament were reviewed. Fifteen patients were included in the noncontact group, in which the spinal cord was free of the ossified lesion after posterior decompression. Twenty-three patients were included in the contact group, in which the spinal cord was not free of the ossified lesion even after posterior decompression. METHODS: The preoperative sagittal alignment of the cervical spine and preoperative maximal thickness of ossification were compared between the two groups. In addition, the morphologic limitations of posterior decompression for ossification of the posterior longitudinal ligament were investigated. RESULTS: The following factors were found to contribute significantly to contact between the spinal cord and ossification of the posterior longitudinal ligament after posterior decompression: 1) lordosis of less than 10 degrees or kyphosis in the preoperative sagittal alignment, and 2) preoperative maximal thickness of ossification of more than 7 mm. CONCLUSIONS: Patients who exhibit significant risk factors for continued contact of the spinal cord should be morphologically considered for anterior decompression.

Adult↗

Impact of longitudinal distance of the cervical spine on the results of expansive open-door laminoplasty.

STUDY DESIGN: A retrospective study in patients who underwent expansive open-door laminoplasty (ELAP) for cervical myelopathy and in whom the cervical alignment was nonlordotic at the final follow-up to analyze the correlation between the longitudinal distance of the cervical spine and surgical results. OBJECTIVES: To determine the impact of longitudinal distance of the cervical spine on surgical results of ELAP and to propose a new concept, the redundant spinal cord, that may influence patient selection for ELAP. SUMMARY OF BACKGROUND DATA: Results in many studies have demonstrated that postoperative cervical alignment has significant effect on surgical results, and spines that are malaligned are thought to deteriorate. The current surgical data showed that not all patients with postoperative malalignment had poor surgical results. Patients with cervical spondylotic myelopathy (CSM) tended to have better clinical results than those with ossification of the posterior longitudinal ligament (OPLL). METHODS: Results in 70 patients who underwent ELAP for cervical myelopathy with postoperative cervical malalignment were investigated. The longitudinal distance index (LDI) was defined as the length of a vertical line between the posteroinferior edges of C2 and C7 divided by the anteroposterior diameter of C4 and was measured on lateral neutral radiographs at final follow-up. Correlation between LDI and surgical results represented by Japanese Orthopedic Association scores and percentage of recovery were analyzed statistically in each patient. RESULTS: Patients with CSM had smaller LDI and better surgical results than those with OPLL. Weak but significant negative correlation was detected between LDI and percentage of recovery, indicating that longitudinal distance of the cervical spine may have some degree of impact on the surgical results of ELAP. CONCLUSION: A decrease in LDI represents shortening of the cervical spine caused by multiple disc degeneration and may influence surgical results of ELAP by inducing redundancy of the spinal cord in patients with postoperative malalignment.

Cervical Vertebrae↗

Quality of life in elderly patients with ossification of the posterior longitudinal ligament.

STUDY DESIGN: A longitudinal cohort study of 216 elderly patients with ossification of the posterior longitudinal ligament for an average of 13 years was performed. OBJECTIVE: To know the quality of life experienced by patients after treatment. SUMMARY OF BACKGROUND DATA: No report is available on the quality of life experienced by elderly patients with ossification of the posterior longitudinal ligament. Because the life prognosis of patients with this condition is relatively good, the quality of life experienced by elderly patients with this disease is an important subject. METHODS: The study participants were 216 elderly patients with ossification of the posterior longitudinal ligament. Conservative therapy was performed for 126 patients, and surgical therapy for 90 patients. Surgery was basically indicated for patients with myelopathy, who were classified using Nurick's grading system. The cumulative survival rate of these patients and their disabilities in daily living were reviewed. The occurrence of fracture resulting from osteoporosis was surveyed, and the relation of such fractures to bone mineral density was examined. RESULTS: The cumulative survival rate of 70-year-old patients exhibiting Nurick Grade 5 severe myelopathy before treatment was 20%, whereas that of patients without myelopathy or those with Grades 1, 2, 3, or 4 myelopathy before treatment was 80%. Patients who underwent surgical therapy for Grade 3 or 4 myelopathy were statistically more likely to be independent of assistance with activities of daily living than those with similar degrees of myelopathy who underwent conservative therapy. The final quality of life was poor for patients with Grade 5 myelopathy at the first examination, regardless of therapeutic method. The prevalence of complication by fracture in patients with ossification of the posterior longitudinal ligament was 1.4% for men and 8.6% for women. The bone mineral density in these patients without myelopathy was significantly higher than in healthy subjects of the same age. CONCLUSION: The study data suggest that surgical treatment should be chosen for patients exhibiting moderate myelopathy to obtain satisfactory quality of life for them over a long period.

Absorptiometry, Photon↗

Occupational recovery after open-door type laminoplasty for patients with ossification of the posterior longitudinal ligament.

STUDY DESIGN: A cross-sectional survey of occupational recovery after surgery with patients who had ossification of the posterior longitudinal ligament. OBJECTIVES: To evaluate occupational recovery after open-door type laminoplasty for patients with ossification of the posterior longitudinal ligament. SUMMARY OF BACKGROUND DATA: The literature contains numerous reports on the surgical results of laminoplasty for ossification of the posterior longitudinal ligament, but very few reports are available on postoperative quality of life, and even fewer on occupational recovery after laminoplasty. METHODS: A cross-sectional survey was conducted of 301 patients with ossification of the posterior longitudinal ligament in the cervical spine who were employed before open-door type laminoplasty. Presurgical occupations were classified into three categories: light sedentary labor, light standing labor, and heavy labor. High-rise workers and professional drivers were analyzed separately. The subjects were rated by occupational category for determining the occupational recovery ratio. Factors analyzed for impact on recovery were pre- and postsurgery severity of myelopathy, duration of myelopathy, age at surgery, gender, and type of ossification of the posterior longitudinal ligament. RESULTS: Of the 301 patients studied, 160 (53%) returned to work. Poor recovery rates were observed for heavy labor, high-rise workers, and professional drivers. The period required for return to work did not significantly differ among occupational categories. Occupation, presurgery severity of myelopathy, and postsurgery severity of myelopathy were significantly correlated with occupational recovery. CONCLUSION: Patients' occupations should be carefully considered when designing postsurgery occupational rehabilitation programs, and patients should receive postoperative advice regarding the suitability of occupation.

Cross-Sectional Studies↗

A Bayesian semiparametric joint hierarchical model for longitudinal and survival data.

This article proposes a new semiparametric Bayesian hierarchical model for the joint modeling of longitudinal and survival data. We relax the distributional assumptions for the longitudinal model using Dirichlet process priors on the parameters defining the longitudinal model. The resulting posterior distribution of the longitudinal parameters is free of parametric constraints, resulting in more robust estimates. This type of approach is becoming increasingly essential in many applications, such as HIV and cancer vaccine trials, where patients' responses are highly diverse and may not be easily modeled with known distributions. An example will be presented from a clinical trial of a cancer vaccine where the survival outcome is time to recurrence of a tumor. Immunologic measures believed to be predictive of tumor recurrence were taken repeatedly during follow-up. We will present an analysis of this data using our new semiparametric Bayesian hierarchical joint modeling methodology to determine the association of these longitudinal immunologic measures with time to tumor recurrence.

Bayes Theorem↗

Methodological challenges associated with patient responses to follow-up longitudinal surveys regarding quality of care.

OBJECTIVE: To illustrate, using empirical data, methodological challenges associated with patient responses to longitudinal surveys regarding the quality of process of care and health status, including overall response rate, differential response rate, and stability of responses with time. DATA SOURCES/STUDY SETTING: Primary patient self-report data were collected from 30,308 patients in 1996 and 13,438 patients in 1998 as part of a two-year longitudinal study of quality of care and health status of patients receiving care delivered by 63 physician organizations (physician groups) across three West Coast states. STUDY DESIGN: We analyzed longitudinal, observational data collected by Pacific Business Group on Health (PBGH) from patients aged 18-70 using a four-page survey in 1996 and a similar survey in 1998 to assess health status, satisfaction, use of services, and self-reported process of care. A subset of patients with self-reported chronic disease in the 1996 study received an enriched survey in 1998 to more fully detail processes of care for patients with chronic disease. DATA COLLECTION/EXTRACTION METHODS: We measured response rate overall and separately for patients with chronic disease. Logistic regression was used to assess the impact of 1996 predictors on response to the follow-up 1998 survey. We compared process of care scores without and with nonresponse weights. Additionally, we measured stability of patient responses over time using percent agreement and kappa statistics, and examined rates of gender inconsistencies reported across the 1996 and 1998 surveys. PRINCIPAL FINDINGS: In 1998, response rates were 54 percent overall and 63 percent for patients with chronic disease. Patient demographics, health status, use of services, and satisfaction with care in 1996 were all significant predictors of response in 1998, highlighting the importance of analytic strategies (i.e., application of nonresponse weights) to minimize bias in estimates of care and outcomes associated with longitudinal quality of care and health outcome analyses. Process of care scores weighted for nonresponse differed from unweighted scores (p<.001). Stability of responses across time was moderate, but varied by survey item from fair to excellent. CONCLUSIONS: Longitudinal analyses involving the collection of data from the same patients at two points in time provide opportunities for analysis of relationships between process and outcomes of care that cannot occur with cross-sectional data. We present empirical results documenting the scope of the problems and discuss options for responding to these challenges. With increasing emphasis in the United States on quality reporting and use of financial incentives for quality in the health care market, it is important to identify and address methodological challenges that potentially threaten the validity of quality-of-care assessments.

Adult↗

Predictors of hand function in older persons: a two-year longitudinal analysis.

OBJECTIVE: To validate a hierarchical model of hand function in older persons, using longitudinal data. DESIGN: Longitudinal observational study (2-year data from an ongoing longitudinal study). SUBJECTS: 689 persons older than age 60, including Continuing Care Retirement Community (n = 230), homebound (n = 204), and ambulatory (n = 255) respondents. Mean age at baseline 76.6 (SD = 8.8). MEASUREMENT: Independent variables included sociodemographics, physician measures of upper joint impairment, self-reported comorbidity, arthritis pain, depression, and anxiety. The dependent variables included grip strength and a timed manual performance test. MAIN RESULTS: Using generalized estimated equations (GEE) to test our hierarchial model, we found that gender and upper extremity joint impairment were the strongest predictors of a longitudinal measure of grip strength. Grip strength, in turn, along with demographics, comorbidity, and a measure of psychological status, was significantly related to timed manual performance. CONCLUSIONS: The longitudinal analyses confirmed a previous cross-sectional finding that upper extremity joint impairment contributes significantly to reduced grip strength, which, in turn, contributes to reduced hand performance on a timed test.

Activities of Daily Living↗

Cross-sectional versus longitudinal estimates of cognitive change in nondemented older people: a CERAD study. Consortium to Establish a Registry for Alzheimer's Disease.

OBJECTIVES: To investigate the effect of increasing age on cognition in nondemented older people. DESIGN: A cross-sectional and longitudinal analysis. PARTICIPANTS: A total of 454 control subjects for Alzheimer's cases from the cohort assembled by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). MEASUREMENT: The Mini-Mental State Examination (MMSE) to assess cognitive function. RESULTS: Cross-sectional estimates were derived by generalized linear models and longitudinal estimates by generalized estimating equations. The cross-sectional model indicated a small but significant decline in MMSE of -.4 points per 10 years. The longitudinal model indicated a small but significant increase in MMSE of about +.6 points per 10 years. Evidence of an early learning effect and nonrandom dropout exists. CONCLUSIONS: The question of "normal" aging can be approached by considering cross-sectional information and, usually separately, longitudinal information. This study does both using recently developed statistical methods. We conclude that there is a small but significant decline in scores on the MMSE with increasing population age. The effect can be masked in longitudinal cohorts by a learning effect (especially early in follow-up) and other factors associated with repeated testing.

Aged↗

Longitudinal dynamics of gene expression and metabolomics in an aging population cohort.

Multiomic profiling provides a comprehensive physiological overview at the molecular level, but understanding of its spatiotemporal dynamics remains limited in human populations. We profiled longitudinal whole-blood gene expression and metabolite levels in 335 females over 8 years. Levels of 5061 genes and 181 metabolites changed over time, with individual trajectories often diverging from population-level trends. Longitudinally variable genes showed cell type specificity and enrichment for aging-relevant pathways, including cardiometabolic and neurodegenerative disorders. Longitudinal trajectories were further shaped by genetics, circadian rhythm, seasonality, and environmental pollutant exposures. Integrative analyses revealed extensive static and time-variable cross-omic connectivity. Longitudinal profiling offers insight into the temporal evolution of age-related conditions at the molecular level, and understanding individual variation within these longitudinal patterns will be essential for future precision medicine approaches.

Female↗