Depletion-of-susceptibles bias in influenza vaccine waning studies: how to ensure robust results.

Vaccine effectiveness studies are subject to biases due to depletion-of-persons at risk of infection, or at especially high risk of infection, at different rates from different groups (depletion-of-susceptibles bias), a problem that can also lead to biased estimates of waning effectiveness, including spurious inference of waning when none exists. An alternative study design to identify waning is to study only vaccinated persons, and compare for each day the incidence in persons with earlier or later dates of vaccination to assess waning in vaccine protection as a function of vaccination time (namely whether earlier vaccination would result in lower subsequent protection compared to later vaccination). Prior studies suggested under what conditions this alternative would yield correct estimates of waning. Here we define the depletion-of-susceptibles process formally and show mathematically that for influenza vaccine waning studies, a randomised trial or corresponding observational study that compares incidence at a specific calendar time among individuals vaccinated at different times before the influenza season begins will not be vulnerable to depletion-of-susceptibles bias in its inference of waning as a function of vaccination time under the null hypothesis that none exists, and will - if waning does actually occur - underestimate the extent of waning. Such a design is thus robust in the sense that a finding of waning in that inference framework reflects actual waning of vaccine-induced immunity. We recommend such a design for future studies of waning, whether observational or randomised.

Safety of zoster vaccine in adults from a large managed-care cohort: a Vaccine Safety Datalink study.

OBJECTIVES: The aim of this study was to examine a large cohort of adults who received the zoster vaccine for evidence of an increased risk of prespecified adverse events requiring medical attention. DESIGN: Two self-comparison approaches, including a case-centred approach and a self-controlled case series (SCCS) analysis were used. SETTING: Eight managed-care organizations participating in the Vaccine Safety Datalink project in the United States. SUBJECTS: A total of 193 083 adults aged 50 and older receiving a zoster vaccine from 1 January 2007 to 31 December 2008 were included. MAIN OUTCOME MEASURES: Prespecified adverse events were identified by aggregated International Classification of Diseases, Ninth Revision (ICD-9) codes in automated health plan datasets. RESULTS: The risk of allergic reaction was significantly increased within 1-7 days of vaccination [relative risk = 2.13, 95% confidence interval (CI): 1.87-2.40 by case-centred method and relative rate = 2.32, 95% CI: 1.85-2.91 by SCCS]. No increased risk was found for the following adverse event groupings: cerebrovascular events; cardiovascular events; meningitis; encephalitis; and encephalopathy; and Ramsay-Hunt syndrome and Bell's palsy. CONCLUSIONS: The results of this study support the findings from the prelicensure clinical trials, providing reassurance that the zoster vaccine is generally safe and well-tolerated with a small increased risk of allergic reactions in 1-7 days after vaccination.

Screening differences and risk of cervical cancer in inflammatory bowel disease.

BACKGROUND: Cervical cancer risk is high among immune suppressed women. AIM: To evaluate inflammatory bowel disease (IBD) with medications and risk of cervical cancer. METHODS: Members of Kaiser Permanente Northern California (KPNC), 15-68 years from 1996 to 2006 with IBD were compared with age-matched women without IBD. Cervical cancer was ascertained using the KPNC Cancer Registry. IBD medications of interest were aminosalicylates (ASA), corticosteroids, immune modulators and infliximab. Odds of cervical cancer were analysed with adjusted logistic regression. The prevalence of Pap smear testing was compared using a log binomial model. RESULTS: Ten cervical cancer cases occurred among 1165 women with IBD and 72 cancers among 12 124 controls. The adjusted odds ratio (OR) of IBD with risk of cervical cancer was 1.45 [95% confidence interval (CI) 0.74-2.84]. Medication ORs were 1.65 for ASA, 2.79 for corticosteroids and 3.45 for immune modulators (all P > 0.05). No cancer case used infliximab. The adjusted absolute increase in Pap smears among IBD women compared to women without IBD was 4% (95% CI 2-5%). CONCLUSIONS: Although a trend of elevated risk for cervical cancer with IBD and IBD medications was observed, it was not statistically significant. Regular cervical cancer screening for women with IBD is recommended.

The prevalence of clinically recognized obsessive-compulsive disorder in a large health maintenance organization.

OBJECTIVE: Little is known about the prevalence of obsessive-compulsive disorder (OCD) as recognized in clinical settings. The authors report data on the prevalence of clinically recognized OCD in a large, integrated, group practice health maintenance organization (HMO). METHOD: The authors examined the database of outpatient diagnoses for the 1.7 million people (age >or=6) in the San Francisco Bay Area and Sacramento who were continuously enrolled in Kaiser Permanente from May 1995 through April 1996. OCD diagnoses were confirmed by chart review. RESULTS: The 1-year prevalence of clinically recognized OCD was 84/100,000 (95% confidence interval: 80-89/100,000), or 0.084%. It varied among the 19 clinics within the HMO but was nowhere higher than 150/100,000. Prevalence was higher among women than among men but was higher among boys than among girls. Above age 65, OCD prevalence decreased markedly in both genders. Period prevalence rates increased by 60% as the length of the study period doubled from 1 to 2 years, more than would be expected for a chronic disease requiring regular care. About three-quarters of both children and adults with OCD had comorbid psychiatric diagnoses; major depression was common in both groups. CONCLUSIONS: Although previously reported prevalences of 1%-3% from community studies may have included many transient or misclassified cases of OCD not requiring treatment, the very low prevalence of clinically recognized OCD in this population suggests that many individuals suffering from OCD are not receiving the benefits of effective treatment.

Comparing the medical expenses of children with Medicaid and commercial insurance in an HMO.

BACKGROUND: In recent years, growing numbers of children with Medicaid have been enrolled in managed care plans nationwide. Yet, large, commercial managed care plans are increasingly discontinuing their participation in Medicaid because of low Medicaid payment rates. OBJECTIVE: To compare the healthcare utilization and costs of children with Medicaid and children with commercial insurance within the same health maintenance organization (HMO). STUDY DESIGN: Retrospective study using electronically captured cost and utilization data. PATIENTS AND METHODS: We compared the healthcare utilization and costs of children with Medicaid (n = 42,636) and children with commercial insurance (n = 159,651) who were members of the same large, nonprofit HMO at any time between January 1, 1995, and December 31, 1997. Medicaid children were grouped as income eligible, medically needy, and blind or disabled. RESULTS: The unadjusted costs of income-eligible, Medicaid-insured children were not significantly different from those of commercially insured children. The medically needy were $25 per month more expensive than commercially insured children (P = 0.02), and the blind or disabled were $213 per month more expensive (P < .01). After adjusting for age and sex, income-eligible children were $5 per month more expensive than children with commercial insurance (P = .07), the medically needy were $20 per month more expensive (P = .02), and the blind or disabled were $216 per month more expensive (P < .01). CONCLUSIONS: The costs of income-eligible, Medicaid-insured children in this HMO were similar to those of commercially insured children, but the costs for the medically needy and the blind and disabled were substantially higher.

Pharmacotherapy of obsessive-compulsive disorder in a health maintenance organization.

The adequacy of pharmacotherapy for patients with obsessive-compulsive disorder (OCD) in a large, prepaid HMO was studied. An analysis was made of the computerized records for December 1, 1994, through April 30, 1998, for members of a Kaiser Permanente plan in northern California who were six years of age or older and had had continuous membership during an index year (May 1, 1995, to April 30, 1996) (1,728 million members). A total of 880 adults and 168 children and adolescents with chart-review-confirmed OCD and a pharmacy benefit were identified. The percentage of patients with an adequate drug trial, defined as > or = 56 days of continuous treatment with a serotonin-reuptake inhibitor or phenelzine at dosages at or above established minimal effective dosages, was determined. Forty-three percent of the adults and 28% of the children and adolescents who were newly diagnosed with OCD in the index year had an adequate trial of medication in the year after their first visit for OCD. By the second six months after the index year, only 75.2% of newly treated adults and 60.9% of newly treated children and adolescents continuing in the health plan filled at least one anti-OCD prescription. During the second follow-up year, these figures fell to 60.4% and 38.9%, respectively. Continuing-care patients filling a prescription in the index year were more likely than newly diagnosed patients to fill prescriptions in the two-year follow-up period, but their treatment still decreased substantially. Despite the typically chronic course of OCD, many patients with OCD who were enrolled in a large HMO appeared not to receive an adequate trial of pharmacotherapy or ongoing pharmacotherapy.

Efficacy of nurse telehealth care and peer support in augmenting treatment of depression in primary care.

BACKGROUND: Primary care treatment of depression needs improvement. OBJECTIVE: To evaluate the efficacy of 2 augmentations to antidepressant drug treatment. DESIGN: Randomized trial comparing usual care, telehealth care, and telehealth care plus peer support; assessments were conducted at baseline, 6 weeks, and 6 months. SETTING: Two managed care adult primary care clinics. PARTICIPANTS: A total of 302 patients starting antidepressant drug therapy. INTERVENTIONS: For telehealth care: emotional support and focused behavioral interventions in ten 6-minute calls during 4 months by primary care nurses; and for peer support: telephone and in-person supportive contacts by trained health plan members recovered from depression. MAIN OUTCOME MEASURES: For depression: the Hamilton Depression Rating Scale and the Beck Depression Inventory; and for mental and physical functioning: the SF-12 Mental and Physical Composite Scales and treatment satisfaction. RESULTS: Nurse-based telehealth patients with or without peer support more often experienced 50% improvement on the Hamilton Depression Rating Scale at 6 weeks (50% vs 37%; P =.01) and 6 months (57% vs 38%; P =.003) and on the Beck Depression Inventory at 6 months (48% vs 37%; P =. 05) and greater quantitative reduction in symptom scores on the Hamilton scale at 6 months (10.38 vs 8.12; P =.006). Telehealth care improved mental functioning at 6 weeks (47.07 vs 42.64; P =.004) and treatment satisfaction at 6 weeks (4.41 vs 4.17; P =.004) and 6 months (4.20 vs 3.94; P =.001). Adding peer support to telehealth care did not improve the primary outcomes. CONCLUSION: Nurse telehealth care improves clinical outcomes of antidepressant drug treatment and patient satisfaction and fits well within busy primary care settings.

Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group.

OBJECTIVE: To determine the efficacy, safety and immunogenicity of the heptavalent CRM197 pneumococcal conjugate vaccine against invasive disease caused by vaccine serotypes and to determine the effectiveness of this vaccine against clinical episodes of otitis media. METHODS: The Wyeth Lederle Heptavalent CRM197 (PCV) was given to infants at 2, 4, 6 and 12 to 15 months of age in a double blind trial; 37,868 children were randomly assigned 1:1 to receive either the pneumococcal conjugate vaccine or meningococcus type C CRM197 conjugate. The primary study outcome was invasive disease caused by vaccine serotype. Other outcomes included overall impact on invasive disease regardless of serotype, effectiveness against clinical otitis media visits and episodes, impact against frequent and severe otitis media and ventilatory tube placement. In addition the serotype-specific efficacy against otitis media was estimated in an analysis of spontaneously draining ears. RESULTS: In the interim analysis in August, 1998, 17 of the 17 cases of invasive disease caused by vaccine serotype in fully vaccinated children and 5 of 5 of partially vaccinated cases occurred in the control group for a vaccine efficacy of 100%. Blinded case ascertainment was continued until April, 1999. As of that time 40 fully vaccinated cases of invasive disease caused by vaccine serotype had been identified, all but 1 in controls for an efficacy of 97.4% (95% confidence interval, 82.7 to 99.9%), and 52 cases, all but 3 in controls in the intent-to-treat analysis for an efficacy of 93.9% (95% confidence interval, 79.6 to 98.5%). There was no evidence of any increase of disease caused by nonvaccine serotypes. Efficacy for otitis media against visits, episodes, frequent otitis and ventilatory tube placement was 8.9, 7.0, 9.3 and 20.1% with P < 0.04 for all. In the analysis of spontaneously draining ears, serotype-specific effectiveness was 66.7%. CONCLUSION: This heptavalent pneumococcal conjugate appears to be highly effective in preventing invasive disease in young children and to have a significant impact on otitis media.

Alcohol drinking patterns and medical care use in an HMO setting.

The objective of this study was to examine the association of medical care use (outpatient visits and hospitalization) with alcohol drinking patterns in a large health maintenance organization (HMO). Data were gathered from a random sample of 10,292 adult respondents through a telephone survey conducted between June 1994 and February 1996. Findings indicate that current nondrinkers with no past history of drinking had higher rates of outpatient visits and hospitalizations than current drinkers. Among current drinkers, medical care use declined slightly as drinking levels increased. Among nondrinkers, those with a drinking history exhibited significantly higher use of outpatient visits and hospital care than nondrinkers with no drinking history and current drinkers. Controlling for demographic and socioeconomic factors, health status, and common medical conditions in multivariate analyses suggests that nondrinkers with a drinking history use more services because they are sicker than other nondrinkers or current drinkers.

The cost of health conditions in a health maintenance organization.

In this retrospective cohort analysis of all adults who were members of Kaiser Permanente, Northern California, between July 1995 and June 1996 (N = 2,076,303), the authors estimated the prevalence, average annual costs per person, and percentage of total direct medical expenditures attributable to each of 25 chronic and acute conditions. Ordinary least squares regression was used to adjust for age, gender, and comorbidities. The costs attributable to the 25 conditions accounted for 78 percent of the health maintenance organization's total direct medical expense for this age-group. Injury accounted for a higher proportion (11.5 percent) of expenditures than any other single condition. Three cardiovascular conditions--ischemic heart disease, hypertension, and congestive heart failure--together accounted for 17 percent of direct medical expense and separately accounted for 6.8 percent, 5.7 percent, and 4.0 percent, respectively. Renal failure ($22,636), colorectal cancer ($10,506), pneumonia ($9,499), and lung cancer ($8,612) were the most expensive conditions per person per year.

Drinking patterns and problems of the "stably insured": a study of the membership of a health maintenance organization.

OBJECTIVE: This article describes drinking patterns and examines the prevalence of heavy drinking and alcohol problems, and their association with other behavioral and social problems within the membership of a health maintenance organization, a setting in which increasing numbers of Americans receive services. METHOD: The sample is representative of the stably insured membership of the Northern California Region of Kaiser Permanente Medical Care Program; i.e., those who have been insured continuously under that plan for 30 months or longer. A telephone survey of the adult membership (N = 10,292) was conducted between June 1994 and February 1996. RESULTS: As in other studies, health and mental health status and smoking were related to drinking levels, with symptoms higher for those in the heaviest drinking group. However, in contrast to studies of those using medical services, demographic characteristics (e.g., young age) were not associated with heavy drinking in this population. When controlling for drug use and drinking, however, women and those reporting any mental health symptom were more likely to report alcohol problems. CONCLUSIONS: Findings suggest that in private managed care populations, particular behavioral indicators may be more important than demographic characteristics in screening for problem drinkers. The identification of individuals who report a mental health symptom, who drink a large number of drinks occasionally or who report any drug use may be important in a health maintenance approach to prevention and case finding.

Cost of care for patients in cancer clinical trials.

BACKGROUND: Information on the costs of medical care for patients enrolled in clinical trials is needed by policymakers evaluating ways to facilitate clinical research in a managed care environment. We examined the direct costs of medical care for patients enrolled in cancer clinical trials at a large health maintenance organization (HMO). METHODS: Costs for 135 patients who entered 22 cancer clinical trials (including 12 breast cancer trials) at Kaiser Permanente in Northern California, from 1994 through 1996 were compared with costs for 135 matched control subjects who were not enrolled in such trials. Cancer registry data and medical charts were used in matching the control subjects to the trial enrollees with respect to cancer site, stage, date of diagnosis, age, sex, and trial eligibility. The direct costs of medical care were compared between trial enrollees and the control subjects for a 1-year period, with data on costs and utilization of services obtained from Kaiser Permanente databases and medical charts. RESULTS: Mean 1-year costs for the enrollees in trials were 10% higher than those for the control subjects ($17 003 per enrollee compared with $15 516 per control subject; two-sided P =.011). The primary component of this difference was a $1376 difference in chemotherapy costs ($4815 per trial enrollee versus $3439 per control subject; two-sided P<.001). Costs for the 11 enrollees in trials that had a bone marrow transplant (BMT) arm were approximately double the costs for their matched control subjects (borderline significance: two-sided P=.054). The $15 041 mean cost for the enrollees in trials without BMT was similar to the $15 186 mean cost for their matched control subjects. CONCLUSIONS: Participation in cancer clinical trials at a large HMO did not result in substantial increases in the direct costs of medical care.

Evaluating hypertension control in a managed care setting.

BACKGROUND: We conducted a retrospective cohort study on a random sample of adult patients with hypertension in a large health maintenance organization to assess the feasibility of documenting blood pressure (BP) control and to compare different measures for defining BP control. METHODS: Three criteria for BP control were assessed: systolic BP less than 140 mm Hg; diastolic BP less than 90 mm Hg; and combined BP control, with systolic BP less than 140 mm Hg and diastolic BP less than 90 mm Hg. Four methods of assessing hypertension control by the above criteria were examined: proportion of patients with BP under control at 75% and 50% or more of their office visits; the mean of all pressures during the study period; and the BP from the last visit during the study period. RESULTS: The proportion of patients meeting each criterion for control was similar whether we used the mean BP for all visits, the last recorded BP, or control at 50% or more of visits. Control rates were substantially lower when the more stringent assessment, 75% of visits, was used. The proportion of patients with combined BP control at 75% or more of their visits was half that of the other methods. CONCLUSIONS: In this health maintenance organization population, results with the use of the simplest approach, the last BP measurement recorded, were similar to results with the mean BP. Our findings indicate that evaluation of BP control in a large health maintenance organization will find substantial room for improvement, and clinicians should be encouraged to be more aggressive in their management of hypertension, especially with regard to the systolic BP, which until recent years has been underemphasized.

Safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate vaccine in infants and toddlers.

OBJECTIVES: The objectives of this study were (1) to determine the safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate (PNCRM7) vaccine in infants and (2) to determine the effect of concurrent hepatitis B immunization during the primary series and the effect of concurrent diphtheria and tetanus toxoid and acellular pertussis [DTaP (ACEL-IMUNE)] and conjugate CRM197 Haemophilus influenzae type b [HbOC (HibTITER) immunization at time of the booster dose on the safety and immunogenicity of PNCRM7and these other concurrently administered vaccines. METHODS: This was a randomized double-blinded study in 302 healthy infants in the Northern California Kaiser Permanente (NCKP) Health Plan. Infants received either PNCRM7 vaccine or meningococcal group C conjugate vaccine as a control at 2, 4 and 6 months of age and a booster at 12 to 15 months of age. Study design permitted the evaluation of immunology and safety of concurrent administration of routine vaccines. Antibody titers were determined on blood samples drawn before and 1 month after the primary series and the booster dose. RESULTS: After the third dose of PNCRM7 geometric mean concentrations (GMCs) ranged from 1.01 for serotype 9V to 3.72 microg/ml for serotype 14. More than 90% of all subjects had a post-third dose titer of > or =0.15 microg/ml for all serotypes, and the percentage of infants with a post-third dose titer of > or =1.0 microg/ml ranged from 51% for type 9V to 89% for type 14. After the PNCRM7 booster dose, the GMCs of all seven serotypes increased significantly over both post-Dose 3 and pre-Dose 4 antibody levels. In the primary series there were no significant differences in GMCs of pneumococcal antibodies between the subjects given PN-CRM7 alone or concurrently with hepatitis B vaccine. At the toddler dose concurrent administration of PNCRM7 and DTaP and HbOC resulted in a near conventional threshold for statistical significance of a post-Dose 4 GMC for serotype 23F [alone 6.75 mirog/ml vs. concurrent 4.11 microg/ml (P = 0.057)] as well as significantly lower antibody GMCs for H. influenza polyribosylribitol phosphate, diphtheria toxoid, pertussis toxin and filamentous hemagglutinin. For all antigens there were no differences between study groups in defined antibody titers that are considered protective. CONCLUSION: We conclude that PNCRM7 vaccine was safe and immunogenic. When this vaccine was administered concurrently at the booster dose with DTaP and HbOC vaccines, lower antibody titers were noted for some of the antigens when compared with the antibody response when PNCRM7 was given separately. Because the GMCs of the booster responses were all generally high and all subjects achieved similar percentages above predefined antibody titers, these differences are probably not clinically significant.

Prostate cancer treatment and ten-year survival among group/staff HMO and fee-for-service Medicare patients.

OBJECTIVE: To compare treatment patterns and the ten-year survival of prostate cancer patients in two large, nonprofit, group/staff HMOs to those of patients receiving care in the fee-for-service health setting. DATA SOURCES/STUDY DESIGN: A cohort of men age 65 and over diagnosed with prostate cancer between 1985 and the end of 1992 and followed through 1994. Subjects (n = 21,741) were ascertained by two population-based tumor registries covering the greater San Francisco-Oakland and Seattle-Puget Sound areas. Linkage of registry data with Medicare claims data and with HMO inpatient utilization data allowed the determination of health plan enrollment and the measurement of comorbid conditions. Multivariate regression models were used to examine HMO versus FFS treatment and survival differences adjusting for sociodemographic and clinical characteristics. PRINCIPAL FINDINGS: Among cases with non-metastatic prostate cancer, HMO patients were more likely than FFS patients to receive aggressive therapy (either prostatectomy or radiation) in San Francisco-Oakland (odds ratio [OR] = 1.69, 95% CI = 1.46-1.96) but not in Seattle (OR = 1.15, 0.93-1.43). Among men receiving aggressive therapy, HMO cases were three to five times more likely to receive radiation therapy than prostatectomy. Overall mortality was equivalent over ten years (HMO versus FFS mortality risk ratio [RR] = 1.01, 0.94-1.08), but prostate cancer mortality was higher for HMO cases than for FFS cases (RR = 1.25, 1.13-1.39). CONCLUSION: Despite marked treatment differences for clinically localized prostate cancer, overall ten-year survival for patients enrolled in two nonprofit group/staff HMOs was equivalent to survival among patients receiving care in the FFS setting, even after adjustment for sociodemographic and clinical characteristics. Similar overall but better prostate cancer-specific survival among FFS patients is most plausibly explained by differences between the HMO and FFS patients in both tumor characteristics and unmeasured patient selection factors.

Survival and treatment for colorectal cancer Medicare patients in two group/staff health maintenance organizations and the fee-for-service setting.

The current study compares treatment use and long-term survival in colorectal cancer patients between Medicare beneficiaries enrolled in two large prepaid group/staff health maintenance organizations (HMOs) and the fee-for-service (FFS) setting. The study is based on 15,352 colorectal cancer cases diagnosed between 1985 and 1992 and followed through 1995. Survival differences between the HMO and FFS cases were assessed using Cox regression. Treatment differences were evaluated using logistic regression. HMO cases had a lower overall mortality than did FFS cases but not a significantly lower colorectal cancer-specific mortality. Use of surgical resection was similar between HMO and FFS cases. However, rectal cancer cases in the HMOs were more likely to receive postsurgical radiation therapy than FFS cases. Superior overall survival in the HMOs may be the result of increased colorectal cancer screening, greater use of adjuvant therapies, and selection of healthier individuals.

A diagnostic aid for detecting (DSM-IV) mental disorders in primary care.

This study was designed to develop and validate a new computerized version of the Symptom Driven Diagnostic System for Primary Care (SDDS-PC) and examine its feasibility in primary care practice. One thousand and one patients (ages 18-70) coming for routine care to Kaiser-Permanente were screened on a self-administered symptom scale for major depression, alcohol and drug dependence, generalized anxiety, panic and obsessive compulsive disorders, and suicidal behavior. The screen was followed up by a brief diagnostic interview, administered by a nurse, which yielded a one-page summary of positive symptoms and a provisional computer-generated diagnosis for the physician. The physician reviewed the summary results and made a diagnosis. The nurse and physician were blind to the screen results. Patients were reinterviewed within 96 hours by a mental health professional (MHP) blind to previous results. The nurses' interviews ranged between 1.5 and 3.5 minutes for a screened positive diagnosis. Agreement between the nurse and physician diagnoses was excellent to moderate. Disagreement was usually in the direction of the physician ruling out major mental disorders in favor of subsyndromal or medical explanations. Only rarely did physicians diagnose disorders not detected by the nurse interview. Agreement between physician and MHP was moderate. Physicians using the SDDS-PC seldom made diagnoses that were not confirmed by the independent assessment of the MHP. The SDDS-PC may facilitate recognition of psychiatric disorders and minimize the physician's time in information gathering.