Jennifer J. Anderson

Effect sizes for interpreting changes in health status

Health status measures are being used with increasing frequency in clinical research. Up to now the emphasis has been on the reliability and validity of these measures. Less attention has been given to the sensitivity of these measures for detecting clinical change. As health status measures are applied more frequently in the clinical setting, we need a useful way to estimate and communicate whether particular changes in health status are clinically relevant. This report considers effect sizes as a useful way to interpret changes in health status. Effect sizes are defined as the mean change found in a variable divided by the standard deviation of that variable. Effect sizes are used to translate “the before and after changes” in a “one group” situation into a standard unit of measurement that will provide a clearer understanding of health status results. The utility of effect sizes is demonstrated from four different perspectives using three health status data sets derived from arthritis populations administered the Arthritis Impact Measurement Scales (AIMS). The first perspective shows how general and instrument-specific benchmarks can be developed and how they can be used to translate the meaning of clinical change. The second perspective shows how effect sizes can be used to compare traditional clinical measures with health status measures in a standard clinical drug trial. The third application demonstrates the use of effect sizes when comparing two drugs tested in separate drug trials and shows how they can facilitate this type of comparison. Finally, our health status results show how effect sizes can supplement standard statistical testing to give a more complete and clinically relevant picture of health status change. We conclude that effect sizes are an important tool that will facilitate the use and interpretation of health status measures in clinical research in arthritis and other chronic diseases.

The effects of specific medical conditions on the functional limitations of elders in the Framingham Study.

OBJECTIVES The purpose of this study was to identify associations between specific medical conditions in the elderly and limitations in functional tasks; to compare risks of disability across medical conditions, controlling for age, sex, and comorbidity; and to determine the proportion of disability attributable to each condition. METHODS The subjects were 709 noninstitutionalized men and 1060 women of the Framingham Study cohort (mean age 73.7 +/- 6.3 years). Ten medical conditions were identified for study: knee osteoarthritis, hip fracture, diabetes, stroke, heart disease, intermittent claudication, congestive heart failure, chronic obstructive pulmonary disease, depressive symptomatology, and cognitive impairment. Adjusted odds ratios were calculated for dependence on human assistance in seven functional activities. RESULTS Stroke was significantly associated with functional limitations in all seven tasks; depressive symptomatology and hip fracture were associated with limitations in five tasks; and knee osteoarthritis, heart disease, congestive heart failure, and chronic obstructive pulmonary disease, were associated with limitations in four tasks each. CONCLUSIONS In general, stroke, depressive symptomatology, hip fracture, knee osteoarthritis, and heart disease account for more physical disability in noninstitutionalized elderly men and women than other diseases.

Obesity and Knee Osteoarthritis: The Framingham Study

STUDY OBJECTIVE To determine whether obesity preceded knee osteoarthritis and was thus a possible cause. DESIGN Cohort study with weight and other important variables measured in 1948 to 1951 (mean age of subjects, 37 years) and knee arthritis evaluated in 1983 to 1985 (mean age of subjects, 73 years). SETTING Population-based participants; a subset (n = 1420) of the Framingham Heart Study cohort. METHODS For those subjects in the Framingham Study having knee radiographs taken as part of the 18th biennial examination (1983 to 1985), we examined Metropolitan Relative Weight, a measure of weight adjusted for height at the onset of the study (1948 to 1951). Relative risks were computed as the cumulative incidence rate of radiographic knee osteoarthritis in the heaviest weight groups at examination 1 divided by the cumulative rate in the lightest 60% weight groups at examination 1. Relative risks were adjusted for age, physical activity level, and uric acid level. RESULTS In 1983 to 1985, 468 subjects (33%) had radiographic knee osteoarthritis. For men, the risk of knee osteoarthritis was increased in those in the heaviest quintile of weight at examination 1 compared with those in the lightest three quintiles (age-adjusted relative risk, 1.51; 95% confidence interval [CI], 1.14 to 1.98); risk was not increased for those in the second heaviest quintile (relative risk, 1.0). The association between weight and knee osteoarthritis was stronger in women than in men; for women in the most overweight quintile at examination 1, relative risk was 2.07 (95% CI, 1.67 to 2.55), and for those in the second heaviest group, relative risk was 1.44 (95% CI, 1.11 to 1.86). This link between obesity and subsequent osteoarthritis persisted after controlling for serum uric acid level and physical activity level, and was strongest for persons with severest radiographic disease. Obesity at examination 1 was associated with the risk of developing both symptomatic and asymptomatic osteoarthritis. CONCLUSIONS These results and other corroborative cross-sectional data show that obesity or as yet unknown factors associated with obesity cause knee osteoarthritis.

Weight Loss Reduces the Risk for Symptomatic Knee Osteoarthritis in Women: The Framingham Study

OBJECTIVE To evaluate the effect of weight loss in preventing symptomatic knee osteoarthritis in women. DESIGN Cohort analytic study. SETTING The Framingham Study, based on a sample of a defined population. PATIENTS Women who participated in the Framingham Knee Osteoarthritis Study (1983 to 1985): Sixty-four out of 796 women studied had recent-onset symptomatic knee osteoarthritis (knee symptoms plus radiographically confirmed osteoarthritis) were compared with women without disease. MEASUREMENTS Recalled date of symptom onset was used as the incident date of disease. Historical weight was defined as baseline body mass index up to 12 years before symptom onset. Change in body mass index was assessed at several intervals before the current examination. Odds ratios assessing the association between weight change and knee osteoarthritis were adjusted for age, baseline body mass index, history of previous knee injury, habitual physical activity level, occupational physical labor, smoking status, and attained education. RESULTS Weight change significantly affected the risk for the development of knee osteoarthritis. For example, a decrease in body mass index of 2 units or more (weight loss, approximately 5,1 kg) over the 10 years before the current examination decreased the odds for developing osteoarthritis by over 50% (odds ratio, 0.46; 95% Cl, 0.24 to 0.86; P = 0.02). Among those women with a high risk for osteoarthritis due to elevated baseline body mass index (greater than or equal to 25), weight loss also decreased the risk (for 2 units of body mass index, odds ratio, 0.41; P = 0.02). Weight gain was associated with a slightly increased risk for osteoarthritis, which was not statistically significant. CONCLUSION Weight loss reduces the risk for symptomatic knee osteoarthritis in women.

Hip fracture and the use of estrogens in postmenopausal women. The Framingham Study.

Abstract To assess the effect of postmenopausal use of estrogens on the subsequent risk of hip fracture, we performed a retrospective cohort study of 2873 women in the Framingham Heart Study. Information obtained at routine biennial examinations about the use of estrogens, body weight, age at menopause, smoking, and alcohol consumption was used to evaluate the risk of hip fracture among postmenopausal women who received estrogens. Hip fractures occurred in 179 postmenopausal women, at a rate that increased exponentially after the age of 50. The risk of fracture was inversely related to weight at all ages. The relative risk of hip fracture in subjects who had taken estrogens at any time was 0.65 after adjustment for age and weight (95 percent confidence interval, 0.44 to 0.98). The adjusted relative risk in women who had taken estrogens within the previous two years was further reduced, to 0.34 (95 percent confidence interval, 0.12 to 0.98). Taking estrogens within four years of menopause also protected ag...

The effect of postmenopausal estrogen therapy on bone density in elderly women

Background Estrogen therapy prevents bone loss in postmenopausal women who take it early in the postmenopausal period. The risk of fracture is highest much later in life, however. We studied whether bone mass in elderly women was affected by earlier estrogen use and how long women needed to take estrogen for it to have a beneficial effect on bone density later in life. Methods In 1988 and 1989, we measured bone mineral density at the femur, spine, shaft of the radius, and ultradistal radius in 670 white women in the Framingham Study cohort (mean age, 76 years; range, 68 to 96). These women had been followed prospectively through menopause and had been asked repeatedly about estrogen therapy. After excluding women who began taking estrogen after a fracture, we investigated whether postmenopausal estrogen therapy affected bone density; in these analyses we adjusted for age, weight, height, cigarette smoking, physical activity, and age at menopause. Results A total of 212 women (31.6 percent) had received es...

High-Dose Melphalan and Autologous Stem-Cell Transplantation in Patients with AL Amyloidosis: An 8-Year Study

Context AL amyloidosis responds poorly to oral chemotherapy and rarely leads to elimination of plasma cell dyscrasia. Amyloid cardiomyopathy is a particularly fatal complication of the disease. Contribution Analysis of consecutive patients with AL amyloidosis from 6 separate trials over 8 years shows that high-dose intravenous melphalan therapy combined with autologous stem-cell transplantation greatly improves duration of survival and ameliorates organ dysfunction. Implications Intravenous melphalan therapy combined with stem-cell transplantation represents a clinically significant improvement in treating AL amyloidosis and shows promise in reversing amyloid cardiomyopathy. The Editors The most common form of systemic amyloidosis in the United States is AL (or primary) amyloidosis. In this disease, amyloid fibrils are derived from monoclonal immunoglobulin light chains that are produced by an underlying clonal plasma cell dyscrasia. Although the burden of plasma cells is generally low, accumulation of amyloid deposits in vital organs leads to progressive disability and death. The median survival of untreated patients after diagnosis is 12 months and less than 5 months for those with cardiomyopathy (1-5). AL amyloidosis is reported to occur in 5 to 12 persons per million per year in the United States; however, death records and autopsy results suggest that the incidence may be higher (6, 7). Treatment with oral melphalan results in a modest increase in median survival but rarely eliminates the plasma cell dyscrasia and is not effective for rapidly progressive disease (8-10). Alternative chemotherapy regimens have not improved survival further (11-15). Promising treatment outcomes observed with high-dose intravenous melphalan and autologous stem-cell transplantation in multiple myeloma (16-19) provided a rationale for testing the hypothesis that this treatment would improve survival for patients with AL amyloidosis. Favorable responses to high-dose melphalan and stem-cell transplantation in patients with AL amyloidosis have been reported in case reports and in small series; however, treatment-related mortality was high in multicenter trials (20-28). Our initial experience with treatment in AL amyloidosis indicated that selected patients can tolerate treatment and that hematologic responses and reversal of amyloid-related organ dysfunction can be achieved (29-32). Since 1994, we have evaluated 701 patients with AL amyloidosis, 312 of whom initiated high-dose melphalan treatment and stem-cell transplantation. This longitudinal study examines survival, hematologic response, and improvement of amyloid-related organ disease in patients who were treated with high-dose melphalan and stem-cell transplantation. We contrast these data with features and survival of a simultaneous cohort of patients who were not eligible for treatment. Methods Patients Between July 1994 and June 2002, 701 consecutive patients with AL amyloidosis were evaluated and clinical data were collected with the approval of the Institutional Review Board of Boston University Medical Center. All patients had biopsy-proven amyloid disease and a documented plasma cell dyscrasia, which was diagnosed by the presence of clonal plasma cells in the bone marrow or a monoclonal gammopathy detected by immunofixation electrophoresis of serum or urine proteins (Figure 1). To exclude another type of systemic amyloidosis and a monoclonal gammopathy of unknown significance, all patients with findings compatible with familial or secondary (AA) amyloidosis were tested by DNA analysis for gene mutations in transthyretin, apolipoprotein A1, fibrinogen, and lysozyme known to be associated with amyloidosis and by immunohistochemistry of the biopsy tissue for AA amyloid fibril deposits (33). Patients with multiple myeloma (bone marrow plasmacytosis 30% or lytic bone lesions) were excluded. In patients older than 70 years of age with cardiomyopathy only, a diagnosis of senile cardiac amyloidosis (caused by wild-type transthyretin) was excluded by immunohistochemical examination of a tissue biopsy specimen using antiserum to transthyretin. All patients were evaluated for degree of organ involvement by physical examination, standardized blood tests, electrocardiography, echocardiography, chest radiography, pulmonary function tests, and a 24-hour urine collection. All patients were evaluated by a hematologist and cardiologist and, when appropriate, by nephrology, pulmonology, gastroenterology, and neurology specialists. Figure 1. Algorithm for patient selection and treatment with high-dose melphalan and stem-cell transplantation. High-Dose Melphalan and Stem-Cell Transplantation Eligibility and Protocols Patients were enrolled in several sequential institutional review boardapproved protocols during the 8-year study period. Eligibility criteria for all protocols required biopsy-proven amyloid disease; evidence of a plasma cell dyscrasia; at least 1 major organ affected by amyloid disease; and minimum measures of cardiac, pulmonary, and performance status (Figure 1). Functional measures included cardiac ejection fraction 0.4 or greater, absence of symptomatic pleural effusions, absence of heart failure or arrhythmia resistant to medical management, oxygen saturation of 95% or greater on room air, lung diffusing capacity of 50% or more of predicted, supine systolic blood pressure of 90 mm Hg or greater, and Southwest Oncology Group performance status score of 2 or less unless limited by neuropathy (on a scale of 0 to 4, reflecting percentage of the day [0%, 25%, 50%, 75%, or 100%] spent in bed or in a chair). Minor variations in eligibility requirements for age, renal function, amount of previous chemotherapy, and time from diagnosis while on some protocols are noted in the following discussion; the number of patients affected is also given. The first protocol (July 1994 to December 1995) enrolled 13 patients 60 years of age or younger with serum creatinine values of 176.8 mol/L (2.0 mg/dL) or less; these patients were treated with melphalan, 200 mg/m2 (29). Subsequent protocols had no restriction for impaired renal function. A second protocol (April 1995 to October 1996) enrolled 28 patients 70 years of age or younger and used a lower dose of melphalan, 100 mg/m2 (31). Two protocols (January 1996 to June 1998) evaluated the use of CD34+-selected stem cells in 16 patients (34). The fifth protocol (October 1996 to September 2000) randomly assigned 100 previously untreated patients to treatment with high-dose melphalan and stem-cell transplantation immediately or after 2 cycles of oral melphalan and prednisone. There was no age limit for this protocol; however, melphalan, 140 mg/m2, was given to patients who were older than 65 years of age or had a cardiac ejection fraction between 0.40 and 0.44. The sixth protocol (November 2000 to the present) has enrolled 29 patients 65 years of age or younger. On this protocol, enough stem cells are collected initially to give a second cycle of chemotherapy within the first year if a complete response has not been achieved after an initial course of melphalan at a dose of 200 mg/m2. Other patients who met eligibility criteria (August 1996 to the present) but were excluded from an active protocol because of previous treatment or time from diagnosis were treated by using the established dosing guidelines. Patients who did not meet eligibility for treatment with high-dose melphalan and stem-cell transplantation were grouped according to reasons for ineligibility and were analyzed for survival. Organ system involvement was defined by physical examination; postural blood pressure determinations; standardized serologic laboratory measurements of kidney, liver, and endocrine function; coagulation studies, including factor X levels; electrocardiography; echocardiography; chest radiography; pulmonary function tests with walking oximetry; and a 24-hour urine collection for protein excretion. Cardiac involvement was defined by septal or posterior wall thickening of 13 mm or greater on echocardiography or a clinical syndrome of congestive heart failure or cardiac arrhythmia in the absence of preexisting cardiac disease. Renal involvement was diagnosed by proteinuria of 500 mg/24 h or greater or an elevated serum creatinine concentration in the absence of other causes of renal disease. Gastrointestinal involvement was diagnosed by involuntary loss of 10% of body weight, unexplained diarrhea, hepatomegaly of 4 cm or more below the right costal margin on physical examination, or alkaline phosphatase level 2 or more times the upper limit of normal values. Peripheral neuropathy was diagnosed by symptoms and physical examination or nerve conduction studies, and autonomic neuropathy was defined by orthostatic hypotensiona decrease in systolic blood pressure of 20 mm Hg or greater with upright posture in euvolemic patients. Soft tissue involvement was diagnosed by clinical evidence of macroglossia, soft tissue or subcutaneous deposits, amyloid arthropathy, lymphadenopathy, or nail dystrophy. Coagulation factor X level was considered deficient if it was 50% or less of normal. Stem-Cell Collection and High-Dose Chemotherapy Peripheral blood stem cells were collected by leukapheresis after mobilization using granulocyte colony-stimulating factor. A minimum yield of 2.0 106 CD34+cells/kg of body weight was required to support high-dose chemotherapy. The patients age and cardiac status and the number of stem cells collected determined the melphalan dose (Figure 1). A dose of 200 mg/m2 was administered to patients who were 65 years of age or younger and who had a cardiac ejection fraction of 0.45 or greater and a stem-cell collection of at least 2.5 106 CD34+cells/kg. A dose of 140 mg/m2 was administered to patients who were older than 65 years of age, who had a cardiac ejection fraction of 0.4 to 0.44, or who had a stem-cell collection of 2.0 to 2.5 106 CD34+cells/k

Iatrogenic illness on a general medical service at a university hospital.

We found that 36% of 815 consecutive patients on a general medical service of a university hospital had an iatrogenic illness. In 9% of all persons admitted, the incident was considered major in that it threatened life or produced considerable disability. In 2% of the 815 patients, the iatrogenic illness was believed to contribute to the death of the patient. Exposure to drugs was a particularly important factor in determining which patients had complications. Given the increasing number and complexity of diagnostic procedures and therapeutic agents, monitoring of untoward events is essential, and attention should be paid to educational efforts to reduce the risks of iatrogenic illness.

Ankylosing spondylitis assessment group preliminary definition of short-term improvement in ankylosing spondylitis.

OBJECTIVE To develop criteria for symptomatic improvement in patients with ankylosing spondylitis (AS), using outcome domain data from placebo-controlled clinical trials of nonsteroidal antiinflammatory drugs (NSAIDs). METHODS Patient data from 5 short-term, randomized, controlled trials were used to assess equivalence, reliability, and responsiveness of multiple items in the 5 outcome domains for AS treatment: physical function, pain, spinal mobility, patient global assessment, and inflammation. At least one measure per domain was responsive (standardized response mean of > 0.5), except for the spinal mobility domain, which was omitted from the criteria. We developed and tested candidate improvement criteria in a random two-thirds subset from the 3 largest trials and used the remaining one-third for validation. These 3 largest trials included 923 patients (631 receiving NSAIDs, 292 in placebo groups). We selected the multiple domain definition that best distinguished NSAID treatment from placebo by chi-square test and that had a placebo response rate of < or = 25%. RESULTS Candidate definitions were changes in single domains and in multiple measure indices, as well as combinations of improvements in multiple domains. Worsening in a domain was defined as a change for the worse of > or = 20% and a net change for the worse of > or = 10 units on a scale of 0-100. Partial remission (for comparison purposes) was defined as an end-of-trial value of < 20/100 in each of the 4 domains. Among 20 candidate criteria, change of > or = 20% and > or = 10 units in each of 3 domains and absence of worsening in the fourth discriminated best in the development subset (51% of patients improved with NSAIDs, 25% with placebo; chi2 = 36.4, P < 0.001). Results were confirmed in the validation subset. Almost all patients satisfying the definition of partial disease remission at the end of the trial had also improved by this criterion. Among all 923 patients, improvement rates using this criterion were 49% for NSAID-treated patients and 24% for placebo-treated patients. CONCLUSION Although further validation using data from new trials is still needed, we conclude that we have developed a clinically valid, easy-to-use measure of short-term improvement in AS.

Treatment of 100 patients with primary amyloidosis: A randomized trial of melphalan, prednisone, and colchicine versus colchicine only

PURPOSE A clinical trial designed to test whether treatment with melphalan, prednisone, and colchicine (MPC) is superior to colchicine (C) alone was performed in patients with primary amyloidosis (AL), a nonmalignant plasma cell dyscrasia. PATIENTS AND METHODS Patients were randomized to MPC or C with stratification according to sex, time from diagnosis to study entry (ie, less than 3 months or 3 to 12 months), and dominant organ system involvement (ie, cardiac, renal, neurologic, or others). Data were gathered monthly from patients, quarterly from physicians, and annually in the Clinical Research Center. One hundred consecutive patients with AL amyloidosis admitted between 1987 and 1992 who met eligibility requirements were treated and followed for a minimum of 18 months. Fifty patients (group A) received daily oral colchicine and 50 patients (group B) received cycles of oral melphalan and prednisone every 6 weeks for 1 year as well as colchicine. RESULTS The principal outcome measure was median survival, which was compared in the two treatment groups and in the subgroups. The overall survival of all patients from study entry was 8.4 months. Comparing group A (C) to group B (MPC), the survival was 6.7 months versus 12.2 months (P = 0.087). Both treatment groups had poor survival for patients in the cardiac subgroup, longest survival in the renal group, and significant differences favoring MPC treatment only in patients whose major system manifestations were neurologic (P = 0.037) or other (P = 0.007). Multivariate analysis showed a strongly significant treatment effect (P = 0.003) and improved survival associated with not having cardiac or gastrointestinal involvement. CONCLUSIONS MPC was advantageous for patients whose major manifestations of amyloid disease were other than cardiac or renal. Better survival regardless of treatment was noted in patients for whom a satisfactory supportive treatment such as transplant or dialysis exists for their organ failure.