California Kaiser Permanente Medical Care Research Articles

Colorectal tumor molecular phenotype and miRNA: expression profiles and prognosis

AbstractMiRNAs regulate gene expression by post-transcriptionally suppressing mRNA translation or by causing mRNA degradation. It has been proposed that unique miRNAs influence specific tumor molecular phenotype. In this paper, we test the hypotheses that miRNA expression differs by tumor molecular phenotype and that those differences may influence prognosis. Data come from population-based studies of colorectal cancer conducted in Utah and the Northern California Kaiser Permanente Medical Care Program. A total of 1893 carcinoma samples were run on the Agilent Human miRNA Microarray V19.0 containing 2006 miRNAs. We assessed differences in miRNA expression between TP53-mutated and non-mutated, KRAS-mutated and non-mutated, BRAF-mutated and non-mutated, CpG island methylator phenotype (CIMP) high and CIMP low, and microsatellite instability (MSI) and microsatellite stable (MSS) colon and rectal tumors. Using a Cox proportional hazard model we evaluated if those miRNAs differentially expressed by tumor phenotype influenced survival after adjusting for age, sex, and AJCC stage. There were 22 differentially expressed miRNAs for TP53-mutated colon tumors and 5 for TP53-mutated rectal tumors with a fold change of >1.49 (or <0.67). Additionally, 13 miRNAS were differentially expressed for KRAS-mutated rectal tumors, 8 differentially expressed miRNAs for colon CIMP high tumors, and 2 differentially expressed miRNAs for BRAF-mutated colon tumors. The majority of differentially expressed miRNAS were observed between MSI and MSS tumors (94 differentially expressed miRNAs for colon; 41 differentially expressed miRNAs for rectal tumors). Of these miRNAs differentially expressed between MSI and MSS tumors, the majority were downregulated. Ten of the differentially expressed miRNAs were associated with survival; after adjustment for MSI status, five miRNAS, miR-196b-5p, miR-31-5p, miR-99b-5p, miR-636, and miR-192-3p, were significantly associated with survival. In summary, it appears that the majority of miRNAs that are differentially expressed by tumor molecular phenotype are MSI tumors. However, these miRNAs appear to have minimal effect on prognosis.

Rate of congenital toxoplasmosis in large integrated health care setting, California, USA, 1998-2012.

To the Editor: Although congenital toxoplasmosis occurs throughout the United States, little information is available about the rates of diagnosed illness in most of the nation, including California. Infection usually occurs by ingestion of undercooked meat and unwashed fruits and vegetables or exposure to soil or water contaminated with cat feces. Congenital transmission can occur when a woman is infected with Toxoplasma gondii during, or just before, pregnancy. Approximately 91% of women of childbearing age in the United States are susceptible to T. gondii infection (1). The United States has a low prevalence of T. gondii infection compared with many areas of the world (2). Severe congenital toxoplasmosis can result in hydrocephalus, retinochoroiditis that affects vision, microcephalus, seizures, hepatosplenomegaly, icterus, psychomotor retardation, and other sequelae (3). Infants with congenital toxoplasmosis are most often asymptomatic at birth; however, when severe symptoms occur, they are usually recognized and the condition diagnosed by the time the child is 2 years of age (3). Our goal was to determine the rate of clinically identified cases of congenital toxoplasmosis in children from birth to 2 years of age within the Northern California Kaiser Permanente Medical Care Program (KPNC) during a 15-year period. KPNC is a group health plan that provides care for >3.2 million residents of northern California. The KPNC membership represents ≈30% of the insured population in the region and is demographically similar to the residents of the counties served except that the very poor and very wealthy are underrepresented (4). We studied live births and infants during 1998–2012, the most recent 15-year period for which records were available and considered complete. We identified potential cases from KPNC electronic medical record databases and confirmed them by reviewing electronic and paper records. The system documents outside services, identified by the corresponding diagnostic codes or laboratory test codes. Eligible case-patients were infants, defined as 1 of 23 specific KPNC laboratory codes for related serologic and PCR tests. We considered clinically confirmed case-patients to be infants with positive T. gondii IgM and/or IgA tests at 12 months of age, PCR–positive results for T. gondii, or diagnosis and care of toxoplasmosis-related conditions. To calculate 95% confidence intervals for rates, we used the exact binomial method. During the 15-year study period, there were 521,655 live births at KPNC facilities and 2,010 infants received >1 test for toxoplasmosis. Ten infants met the potential case criteria of diagnostic codes; no additional patients met any of the case criteria by age 2 years. After electronic and paper charts were reviewed, 2 cases of congenital toxoplasmosis were confirmed. One case was diagnosed in 2003, the other in 2011. Both case-patients were girls: 1 was of Hispanic ethnicity and the other was of mixed Filipino-White heritage; both had IgG persistently detected beyond 12 months of age and were monitored clinically for retinochoroiditis. Their charts contained no information regarding maternal exposure or risk factors. During the 15-year period, the rate of diagnosed congenital toxoplasmosis was 3.8 (95% CI 1.5–9.2) per million live births. There were no infant deaths for which congenital toxoplasmosis was recorded as a cause. We were unable to study fetal deaths because the corresponding cause-of-death codes were not readily available. Historically, the lowest prevalence of T. gondii infection has been recorded in the western United States (5). The rate of clinically apparent congenital toxoplasmosis in this study was lower than that found during the late 1980s through early 1990s in the New England Newborn Screening Program initially after birth (2 per 521,555 live births [3.8 per million] versus 5 per 635,000 live births [7.9 per million], respectively) (6). However, the prevalence of T. gondii infection has decreased in the United States since the 1990s (1). Our study is subject to several limitations. Our approach would only detect clinically apparent cases, and the results should be considered a minimal estimate of congenital infection. Some cases may not have been recorded in the electronic system, but this omission is not likely for severe illness, repeated hospital or clinic visits, or outside consultation. The small number of cases makes the rate of diagnosed congenital toxoplasmosis somewhat imprecise; a few missed cases would increase the rate considerably. In addition, we were not able to evaluate fetal deaths; however, stillbirth is reportedly a rare complication of congenital toxoplasmosis (7). Although we found a low rate of diagnosed congenital toxoplasmosis in northern California, population-based studies to evaluate rates of the disease in other geographic areas would be beneficial.

Effectiveness of telaprevir and boceprevir triple therapy for patients with hepatitis C virus infection in a large integrated care setting.

In 2011, the FDA approved telaprevir (TVR) and boceprevir (BOC) for use with pegylated interferon and ribavirin to treat hepatitis C virus (HCV) genotype 1. We aimed to evaluate the real-world application, tolerability, and effectiveness of TVR- and BOC-based HCV treatment in a large integrated care setting. We utilized Northern California Kaiser Permanente Medical Care Program (KPNC) electronic databases and medical records to study the experience of all KPNC patients who initiated TVR or BOC from June 2011 to March 2012. Compared with the pool of 5,194 treatment-eligible patients, the 352 treatment initiators were more likely to be cirrhotic (24 vs. 10%, p < 0.001) and treatment-experienced (44 vs. 22%, p < 0.001). Among the treatment initiators, 211 received TVR and 141 BOC. Overall, 31% discontinued treatment prematurely; 16% of patients stopped treatment early because of side effects. One patient with cirrhosis died of sepsis during treatment. Premature discontinuation was highest among TVR-treated cirrhotic patients (58%). Sustained virologic response (SVR) was achieved in 55% overall and was similar comparing the TVR (56%)- and BOC (53%)-treated groups. The only independent predictors of treatment failure were cirrhosis at baseline [odds ratio (OR) for SVR 0.44, p = 0.004] and prior partial or null response (OR for SVR 0.57, p = 0.02). In the initial application of TVR and BOC, patients with cirrhosis and prior treatment failure were prioritized for treatment. In this real-world experience, most patients successfully completed a full treatment course. However, side effect-related premature discontinuations were common, and SVR rates were lower than reported in clinical trials.

Characteristics and management of patients with chronic hepatitis B in an integrated care setting.

Few population-based studies have described characteristics and management of patients with chronic hepatitis B (CHB) in the USA. We retrospectively studied adults with CHB in the Northern California Kaiser Permanente Medical Care Program (KPNC) from July 2009 to December 2010 (n = 12,016). Laboratory tests, treatment patterns, and hepatocellular carcinoma (HCC) surveillance were ascertained during a "recent" 18-month study window (July 2009-December 2010), or as "ever" based on records dating to 1995. The mean age was 49 years; 51 % were men, 83 % Asian, and 87 % KPNC members >5 years. Overall, 51 % had ≥ 1 liver-related visit, 14 % with gastroenterology or infectious disease specialists, and 37 % with primary care providers (PCP) only. Less than 40 % of patients had both hepatitis B virus (HBV) DNA and ALT testing conducted recently, while 56 % of eligible patients had received HCC surveillance. Recent laboratory testing and HCC surveillance were more frequent in patients seen by a specialist versus PCP only (90 vs. 47 % and 92 vs. 73 %, respectively, p values <0.001). During the study period, 1,649 (14 %) received HBV treatment, while 5 % of untreated patients had evidence of treatment eligibility. Among 599 patients newly initiated on HBV therapy, 76 % had guideline-based indications for treatment. Most patients initiated on HBV treatment met eligibility, and very few patients with evidence of needing treatment were left untreated. However, monitoring of ALT and HBV DNA levels, as well as HCC surveillance, were not frequent, underestimating the proportion of patients that warranted HBV therapy. Viral monitoring and cancer surveillance are therefore important targets for improving the scope of CHB care in the community setting.

Abstract P107: Association of Longitudinal Change and Fluctuation in QT Interval with Cardiovascular Outcomes: A Cohort Study in a Managed Care Setting

Purpose. Both long and short QT intervals are associated with life-threatening cardiac arrhythmias and adverse cardiovascular (CV) events, but prior studies have typically relied on a single baseline measure of the QT interval. We examined the prospective association of within-person change and fluctuation in QT length over time with subsequent CV outcomes and all-cause mortality in a managed care setting. Methods. We assembled a cohort of 187,901 Northern California Kaiser Permanente Medical Care Program (KPMCP) members who underwent three or more standard 12-lead ECGs as part of regular care between 1995 and 2008. Cohort-specific log-linear models stratified by gender, age and race/ethnicity were used to correct raw QT measurements for heart rate (QTc). Non-fatal and fatal CV outcomes and all-cause mortality were identified between the last ECG and right censoring event (CV event, death, termination of health plan membership or 12/31/2009; the median [SD] follow-up time was 4.1 [3.7] years). Cox regression models adjusting for age, gender, race/ethnicity, hypertension, diabetes, hyperlipidemia, smoking status and average QTc were used to simultaneously generate hazard ratios and 95% CI for tertiles 1 and 3 (versus tertile 2) of the linear slope of QTc (change in ms per year) and for tertiles 2 and 3 (versus tertile 1) of the root mean square error of QTc (RMSE, variability about the linear slope in ms). Results. The mean QTc slope and RMSE were +2.2 ms/year and 15.3 ms in men and +1.4 ms/year and 14.3 ms in women, respectively. In fully-adjusted models, the sex-specific tertile 3 of the QTc slope was associated with increased hazard of acute coronary syndrome (Number of events; Hazard Ratio; 95% Confidence Interval) (17,920; 1.34; 1.30-1.39), ischemic stroke (11,716; 1.30; 1.25-1.36), heart failure (42,909; 1.47; 1.44-1.51), cardiac arrest (4,700; 1.67; 1.55-1.79) and all-cause mortality (72,392; 1.43;1.40-1.45). In turn, the sex-specific tertile 3 of the RMSE was associated with increased hazard of heart failure (1.34;1.31-1.37), cardiac arrest (1.19;1,11-1.28) and all-cause mortality (1.06;1.04-1.08). Conclusions. In an insured population that underwent multiple ECGs, both linear increase and fluctuation of QTc over time were significantly and independently associated with adverse CV outcomes. Whether these associations are causal or represent confounding effects of medications warrant further research.

Total Serum Bilirubin Exceeding Exchange Transfusion Thresholds in the Setting of Universal Screening

To describe the incidence and predictors of total serum bilirubin (TSB) levels that meet or exceed American Academy of Pediatrics (AAP) exchange transfusion (ET) thresholds in the setting of universal screening. We conducted a retrospective cohort analysis of electronic data on 18089 newborns ≥35 weeks gestation born at Northern California Kaiser Permanente Medical Care Program hospitals implementing universal TSB screening in 2005 to 2007, with chart review for subjects with TSB levels reaching the AAP threshold for ET. The outcome developed in 22 infants (0.12%); 14 (63.6%) were <38 weeks gestation. Only one infant received an ET; none of the infants had documented sequelae. The first TSB was at least high-intermediate risk on the AAP risk-nomogram for all 22 infants and high-risk for those ≥38 weeks, but was less than the phototherapy level in 15 infants (68%). Of these 15 infants, 2 failed phototherapy and 13 did not have a TSB repeated in <24 hours. However, re-testing all infants at high-intermediate risk or greater would have required 2166 additional bilirubin tests. Screening was sensitive but not specific for predicting exchange threshold.

Underimmunization at discharge from the neonatal intensive care unit

The objectives of this study are to determine immunization rates at discharge from the neonatal intensive care unit (NICU) among infants 2 months of age and above and to evaluate risk factors for underimmunization. A retrospective cohort study was performed for infants in six NICUs in the Northern California Kaiser Permanente Medical Care Program. Immunization status at discharge was determined for all infants discharged on or after age 60 days. Logistic regression was used to identify risk factors for underimmunization at the time of discharge. Of 668 infants discharged on or after age 60 days from the NICU, 51% were up-to-date for routine immunizations. Twenty-seven percent of infants had received no vaccines. Factors associated with higher immunization rates at discharge include history of mechanical ventilation, congenital heart disease and a diagnosis of apnea or bronchopulmonary dysplasia during the NICU stay, whereas surgery was associated with lower immunization rates. A significant proportion of infants discharged on or after 2 months of age in the NICU in this health system was unimmunized or underimmunized at discharge. Further efforts should be made to improve immunization rates prior to discharge.

Lessons From Practice

To characterize the risks of cervical intraepithelial neoplasia 3 (CIN 3) and cancer in women aged 21 to 24 with human papillomavirus (HPV)-positive atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL) screening results in routine clinical practice. Quality assurance databases containing records of screening test and histologic findings from the Regional Laboratory of the Northern California Kaiser Permanente Medical Care Program were reviewed. Numbers of LSIL and HPV-positive ASC-US results and associated cancers and CIN 3 in women aged 21 to 24 during 2003 to 2007 were tabulated, and the corresponding risks were calculated overall and by year of age. During the 5-year period from 2003 to 2007, 1,620 HPV-positive ASC-US and 2,175 LSIL were diagnosed in women aged 21 to 24, for which corresponding histologic finding is available. No invasive cancers were detected in association with LSIL and HPV-positive ASC-US screening results in this age group during this period. The risk of cancer was therefore 0% (95% CI = 0.00%-0.10%). The risk of CIN 3 associated with an HPV-positive ASC-US was 2.90% (95% CI = 2.14%-3.84%), with LSIL was 2.44% (95% CI = 1.83%-3.18%), and, for the 2 combined, the risk was 2.64% (95% CI = 2.15%-3.20%). The risk of CIN 3 and cancer is low enough that management of women aged 21 to 24 with ASC-US and LSIL smears without immediate colposcopy should be considered, as is currently recommended for women aged 20 and younger.

Prevalence and Predictors of Perinatal Hemorrhagic Stroke

Source: Armstrong-Well J, Johnston SC, Wu YW, et al. Prevalence and predictors of perinatal hemorrhagic stroke: results from the Kaiser Pediatric Stroke Study. Pediatrics.2009;123(3):823–828; doi:10.1542/peds.2008–0874To determine the prevalence and predictors of perinatal hemorrhagic stroke (PHS), investigators from the University of California at San Francisco and Kaiser Permanente Medical Program in Oakland, CA performed a case-control study nested within a cohort of infants born from 1993 to 2003 in the Northern California Kaiser Permanente Medical Care Program. Cases of symptomatic perinatal hemorrhagic stroke and arterial ischemic stroke in neonates older than 28 weeks’ gestational age through 28 days of life were retrospectively identified through electronic searches of databases and confirmed by medical chart review. Cases of pure intraventricular hemorrhage were excluded. Three controls for each case were randomly selected from the cohort, matched by year and medical facility of birth.Among 323,532 live births, 20 cases of PHS were identified (19 intracerebral hemorrhage and one subarachnoid hemorrhage). Three case infants (15%) were premature (31 weeks gestation), and five (25%) were postmature; three case infants (15%) had birth weights <2500 g and three had birth weights of >4000 g. The prevalence of PHS was 6.2 in 100,000 live births, or 1 in 16,000 live births. In comparison, 93 cases of perinatal arterial ischemic stroke were identified, a prevalence of 29 in 100,000 or 1 in 3,500 live births.Cases of PHS presented with encephalopathy (100%) and seizures (65%). The etiology was idiopathic in 15 (75%), thrombocytopenia in 4 (20%), and cavernous malformation in 1 (5%). Neuroimaging abnormalities were unifocal in 14 of 19 (74%) and unilateral in 15 (83%). Lesions were more likely to be left-sided (56%) than right-sided (28%) or bilateral (16%), and more likely to be parietal (47%) and frontal (37%) than temporal (16%) in location.Univariate predictors of PHS included fetal distress, emergent cesarean delivery, prematurity, and postmaturity but not birth weight or difficult vaginal delivery. Fetal distress and postmaturity continued to be independent predictors of PHS in a multivariate model. The authors conclude that fetal distress and postmaturity (although not large birth weight) are independent predictors of perinatal hemorrhagic stroke.Dr. Millichap has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Published reports have classified and defined the prevalence and risk factors for perinatal arterial ischemic stroke,1,2 but PHS has not been studied as frequently.3 The risk associated with postmaturity in the Kaiser Permanente study is not explained by macrosomia or obstetrical trauma. No maternal health factors predicted PHS.In contrast, previously reported risk factors for perinatal arterial ischemic stroke include chorioamnionitis, prolonged rupture of membranes, preeclampsia, placental thrombi, intrauterine growth retardation, prothrombotic and hematological factors, congenital heart disease with cerebral thromboembolism, infection, and inflammation.4In the current study, PHS most commonly presented with encephalopathy or seizures. In comparison, congenital hemiplegia and epilepsy are the most common neurologic deficits resulting from perinatal arterial ischemic stroke.4 Preterm children with a history of perinatal cerebral hemorrhage and severe brain injury have delays in cognitive function and require educational intervention at 12 years of age.5In a retrospective study of 85 infants and children (age range 7 days to 17 years) with nontraumatic intracranial hemorrhage and stroke at Children’s Hospital Columbus, OH,6 location of hemorrhage was subarachnoid in 10 (12%), intraparenchymal in 61 (72%), and subdural in 14 (16%). Risk factors included intracranial vascular anomalies in 24 (28%; arteriovenous malformation [AVM] in 11), congenital heart disease in 14 (16%), and brain tumor in 13 (15%). Infection was associated in five (6%) cases, and coagulation deficiencies in four (5%). Mortality was 34%. Of 48 survivors with follow-up information, 26 (54%) had no deficits, and 22 (46%) had mild deficits.Another study of 251 patients with childhood stroke (aged 1 month through 16 years) admitted to Beijing Children’s Hospital, China, from 1996 to 2006 found that arterial ischemic stroke accounted for the majority of cases (62.5%) and hemorrhagic stroke for 37.5%.7 Vitamin K deficiency was a major etiology of hemorrhagic stroke in China, diagnosed in 72 (76.6%) of 94 cases, most occurring in breastfed infants who had received no vitamin K after birth. Cerebral vascular abnormality was present in seven (7%) cases, and AVM in six. Infection played a role in 10%, including viral encephalitis, varicella zoster, mycoplasma, and Epstein-Barr virus infections. Etiological factors associated with childhood hemorrhagic stroke in China differ from those reported in Western countries, where AVM is the most frequent cause.In contrast to childhood stroke, the mechanisms underlying PHS remain an enigma, but the association with fetal distress suggests that prenatal factors may be paramount.

Tumor markers and rectal cancer: Support for an inflammation‐related pathway

Inflammation may be a key element in the etiology of colorectal cancer. In our study, we examine associations between factors related to inflammation and specific rectal cancer mutations. A population-based study of 750 rectal cancer cases with interview and tumor DNA were compared to 1,205 population-based controls. Study participants were from Utah and the Northern California Kaiser Permanente Medical Care Program. Tumor DNA was analyzed for TP53 and KRAS2 mutations and CpG Island methylator phenotype. We assessed how these tumor markers were associated with use of anti-inflammatory drugs, polymorphisms in the IL6 genes (rs1800795 and rs1800796) and dietary antioxidants. Ibuprofen-type drugs, IL6 polymorphisms (rs1800796) and dietary alpha-tocopherol and lycopene significantly altered likelihood of having a TP53 mutation. This was especially true for TP53 transversion mutations and dietary antioxidants (OR for beta-carotene 0.51 95% CI 0.27, 0.97, p trend 0.03; alpha-tocopherol 0.41 95% CI 0.20, 0.84, p trend 0.02) Beta-carotene and ibuprofen significantly altered risk of KRAS2 tumors. The associations between lutein and tocopherol and TP53 and KRAS2 mutations were modified by IL6 genotype. These results suggest that inflammation-related factors may have unique associations with various rectal tumor markers. Many factors involved in an inflammation-related pathway were associated with TP53 mutations and some dietary factors appeared to be modified by IL6 genotype.

Infant Functional Status: The Timing of Physiologic Maturation of Premature Infants

To describe the maturation of physiologic milestones in preterm infants born between 24 and 32 weeks' gestational age. We abstracted daily physiologic maturity information on 865 infants born at < or =32 weeks' gestation in the Northern California Kaiser Permanente Medical Care Program between 1998 and 2001. Data included ventilator and incubator settings, body temperature, apnea and bradycardia spells, use of methylxanthines, feeding method, and requirements for intravenous fluids. Multivariable quantile regression models identified risk factors associated with longer postmenstrual age to achieve various physiologic milestones, including time to full oral feeding, time to wean from supplemental heat, the last day with an apnea or bradycardia episode, the last day on methylxanthine medications, and the last day on supplemental oxygen. Most milestones were achieved between 34 and 36 weeks' postmenstrual age, although there were wide variations between patients. In most cases, feeding and oxygen milestones were achieved last. For each milestone there was a monotonic relationship between birth gestational age and the median achievement postmenstrual age. However, bronchopulmonary dysplasia and necrotizing enterocolitis strongly influenced these results in infants of younger gestational age. This study provides epidemiologic data describing the achievement of basic physiologic milestones that influence the discharge of a premature infant. This work serves as an additional contribution in the development of algorithms to monitor the progress of neonates through their initial hospitalization and provides a reference population for future interventions to improve the physiologic maturation of prematurely born infants.

Predictors of Perinatal Hemorrhagic Stroke

The prevalence and predictors of perinatal hemorrhagic stroke were determined in a case-control study of infants born from 1993 to 2003 in the Northern California Kaiser Permanente Medical Care Program, Oakland, CA, and reported from the University of California, San Francisco, CA.

Time to send the preemie home? Additional maturity at discharge and subsequent health care costs and outcomes.

To determine whether longer stays of premature infants allowing for increased physical maturity result in subsequent postdischarge cost savings that help counterbalance increased inpatient costs. One thousand four hundred and two premature infants born in the Northern California Kaiser Permanente Medical Care Program between 1998 and 2002. Using multivariate matching with a time-dependent propensity score we matched 701 "Early" babies to 701 "Late" babies (developmentally similar at the time the earlier baby was sent home but who were discharged on average 3 days later) and assessed subsequent costs and clinical outcomes. Late babies accrued inpatient costs after the Early baby was already home, yet costs after discharge through 6 months were virtually identical across groups, as were clinical outcomes. Overall, after the Early baby went home, the Late-Early cost difference was $5,016 (p<.0001). A sensitivity analysis suggests our conclusions would not easily be altered by failure to match on some unmeasured covariate. In a large integrated health care system, if a baby is ready for discharge (as defined by the typical criteria), staying longer increased inpatient costs but did not reduce postdischarge costs nor improve postdischarge clinical outcomes.

Prevalence and Predictors of Perinatal Hemorrhagic Stroke: Results From the Kaiser Pediatric Stroke Study

Predictors for perinatal arterial ischemic stroke include both maternal and intrapartum factors, but predictors of perinatal hemorrhagic stroke have not been studied. We sought to determine both the prevalence and predictors of perinatal hemorrhagic stroke within a large, multiethnic population. We performed a case-control study nested within the cohort of all infants born from 1993 to 2003 in the Northern California Kaiser Permanente Medical Care Program, a health maintenance organization providing care for >3 million members. Cases of symptomatic perinatal hemorrhagic stroke and perinatal arterial ischemic stroke in neonates (28 weeks' gestational age through 28 days of life) were identified through electronic searches of diagnosis and radiology databases and confirmed by medical chart review. Three controls per case were randomly selected and matched on birth year and facility. This analysis included cases of perinatal hemorrhagic stroke (intracerebral hemorrhage or subarachnoid hemorrhage, excluding pure intraventricular hemorrhage) and all controls. Predictors of perinatal hemorrhagic stroke were assessed by using logistic regression, adjusting for the matching criteria. Among 323 532 live births, we identified 20 cases of perinatal hemorrhagic stroke (19 intracerebral hemorrhage and 1 subarachnoid hemorrhage), which yielded a population prevalence for perinatal hemorrhagic stroke of 6.2 in 100 000 live births. Cases presented with encephalopathy (100%) and seizures (65%). Perinatal hemorrhagic stroke was typically unifocal (74%) and unilateral (83%). Etiologies included thrombocytopenia (n = 4) and cavernous malformation (n = 1); 15 (75%) were idiopathic. Univariate predictors of perinatal hemorrhagic stroke included male gender, fetal distress, emergent cesarean delivery, prematurity, and postmaturity but not birth weight. When entered into a multivariate model, fetal distress and postmaturity continued to be independent predictors. Fetal distress is an independent predictor of perinatal hemorrhagic stroke, perhaps suggesting a prenatal event. Postmaturity also predicts perinatal hemorrhagic stroke, an association not explained by large birth weight in our study.

Increased Risk of Adverse Neurological Development for Late Preterm Infants

To assess the risks of moderate prematurity for cerebral palsy (CP), developmental delay/mental retardation (DD/MR), and seizure disorders in early childhood. Retrospective cohort study using hospitalization and outpatient databases from the Northern California Kaiser Permanente Medical Care Program. Data covered 141 321 children > or =30 weeks born between Jan 1, 2000, and June 30, 2004, with follow-up through June 30, 2005. Presence of CP, DD/MR, and seizures was based on International Classification of Diseases, Ninth Revision codes identified in the encounter data. Separate Cox proportional hazard models were used for each of the outcomes, with crude and adjusted hazard ratios calculated for each gestational age group. Decreasing gestational age was associated with increased incidence of CP and DD/MR, even for those born at 34 to 36 weeks gestation. Children born late preterm were >3 times as likely (hazard ratio, 3.39; 95% CI, 2.54-4.52) as children born at term to be diagnosed with CP. A modest association with DD/MR was found for children born at 34 to 36 weeks (hazard ratio, 1.25; 95% CI, 1.01-1.54), but not for children in whom seizures were diagnosed. Prematurity is associated with long-term neurodevelopmental consequences, with risks increasing as gestation decreases, even in infants born at 34 to 36 weeks.

The Epidemiology of Newly Diagnosed Chronic Liver Disease in Gastroenterology Practices in the United States: Results From Population-Based Surveillance

Chronic liver disease (CLD) is an important cause of morbidity and mortality, but the epidemiology is not well described. We conducted prospective population-based surveillance to estimate newly diagnosed CLD incidence, characterize etiology distribution, and determine disease stage. We identified cases of CLD newly diagnosed during 1999-2001 among adult county residents seen in any gastroenterology practice in New Haven County, Connecticut; Multnomah County, Oregon; and Northern California Kaiser Permanente Medical Care Program (KPMCP, Oakland, California [total population 1.48 million]). We defined CLD as abnormal liver tests of at least 6 months' duration or pathologic, clinical, or radiologic evidence of CLD. Consenting patients were interviewed, a blood specimen obtained, and the medical record reviewed. We identified 2,353 patients with newly diagnosed CLD (63.9 cases/100,000 population), including 1,225 hepatitis C patients (33.2 cases/100,000). Men aged 45-54 yr had the highest hepatitis C incidence rate (111.3/100,000). Among 1,040 enrolled patients, the median age was 48 yr (range 19-86 yr). Hepatitis C, either alone (442 [42%]) or in combination with alcohol-related liver disease (ALD) (228 [22%]), accounted for two-thirds of the cases. Other etiologies included nonalcoholic fatty liver disease (NAFLD, 95 [9%]), ALD (82 [8%]), and hepatitis B (36 [3%]). Other identified etiologies each accounted for <3% of the cases. A total of 184 patients (18%) presented with cirrhosis, including 44% of patients with ALD. Extrapolating from this population-based surveillance network to the adult U.S. population, approximately 150,000 patients with CLD were diagnosed in gastroenterology practices each year during 1999-2001. Most patients had hepatitis C; heavy alcohol consumption among these patients was common. Almost 20% of patients, an estimated 30,000 per year, had cirrhosis at presentation. These results provide population-level baseline data to evaluate trends in identification of patients with CLD in gastroenterology practices.

Lack of Association between Age at Varicella Vaccination and Risk of Breakthrough Varicella, within the Northern California Kaiser Permanente Medical Care Program

Varicella vaccine currently is recommended for children between 12 and 18 months of age. However, rates of breakthrough varicella have been reported to be higher among children vaccinated before 14 or 15 months of age and to increase with time since vaccination. An ongoing study at the Northern California Kaiser Permanente Medical Care Program is evaluating vaccine efficacy in 7585 children vaccinated with Varivax in 1995, when they were between 12 and 23 months of age. Cases of chickenpox are identified by telephone interviews with each child's parent(s) every 6 months. Mean age at varicella onset and mean time from vaccination to onset were calculated on the basis of age, in months, at vaccination. Logistic regression was used to test for trend, and the chi2 test was used to test for differences in rates of breakthrough varicella by age. Over the first 8 years of the study, a total of 1161 cases of breakthrough varicella were reported, for an average rate of 21.7 cases/1000 person-years. Vaccine effectiveness was 83.6% at year 8. The rate of breakthrough varicella did not change for each additional month of age at vaccination (P = .864), and no difference in the rate of breakthrough varicella was found between children vaccinated at <15 months of age and those vaccinated at > or =15 months of age. Our data do not show a difference in vaccine effectiveness with age at vaccination and thus support the current recommendations for initial vaccination between 12 and 18 months of age.

Risk Factors for Developing Apnea After Immunization in the Neonatal Intensive Care Unit

Among hospitalized NICU infants, preimmunization apnea is a well-recognized predictor of postimmunization apnea. However, predictors for postimmunization apnea among NICU infants without preimmunization apnea have not been investigated. Using a large NICU database in the Northern California Kaiser Permanente Medical Care Program, we abstracted NICU charts of infants who were hospitalized for > or = 53 days and who were also immunized, capturing preimmunization (24 hours before immunization) and postimmunization (48 hours after immunization) events. We assessed factors associated with postimmunization apnea by using multivariate logistic regression. Of 16,146 infants admitted to the NICU, 557 received > or = 1 vaccine and 497 met the criteria for study entry. All infants with preimmunization apnea (n = 27) and all except 3 infants with postimmunization apnea (n = 65) had gestational ages of < 31 weeks. Multivariate analyses revealed preimmunization apnea as the most important predictor of postimmunization apnea, although higher 12-hour Score for Neonatal Acute Physiology II and age of < 67 days (mean cohort age) were also associated. Multivariate analysis exclusively among infants without preimmunization apnea similarly found elevated Score for Neonatal Acute Physiology II, age of < 67 days, and weight of < 2000 g to be associated with postimmunization apnea. Forty-nine infants without preimmunization apnea and with > or = 1 apnea predictor were discharged within 48 hours after immunization; 2 were subsequently readmitted because of apnea. For infants in the NICU without apnea during the 24 hours immediately before immunization, younger age, smaller size, and more severe illness at birth are important predictors of postimmunization apnea.

COPD and Incident Cardiovascular Disease Hospitalizations and Mortality: Kaiser Permanente Medical Care Program

To determine the relationship between diagnosed and treated COPD and the incidence of cardiovascular disease (CVD) hospitalization and mortality. Retrospective matched cohort study. Northern California Kaiser Permanente Medical Care Program (KPNC), a comprehensive prepaid integrated health-care system. Case patients (n = 45,966) were all KPNC members with COPD who were identified during a 4-year period from January 1996 through December 1999. An equal number of control subjects without COPD were selected from KPNC membership and were matched for gender, year of birth, and length of KPNC membership. Follow-up conducted for hospitalization and mortality from CVD end points through December 31, 2000. CVD study end points included cardiac arrhythmias, angina pectoris, acute myocardial infarction, congestive heart failure (CHF), stroke, pulmonary embolism, all of the aforementioned study end points combined, other CVD, and all CVD end points. The mean follow-up time was 2.75 years for case patients and 2.99 years for control subjects. The risk of hospitalization was higher in COPD case patients than in control subjects for all CVD hospitalization and mortality end points. The relative risk (RR) for hospitalization for the composite measure of all study end points was 2.09 (95% confidence interval [CI], 1.99 to 2.20) after adjustment for gender, preexisting CVD study end points, hypertension, hyperlipidemia, and diabetes, and ranged from 1.33 (stroke) to 3.75 (CHF). The adjusted RR for mortality for the composite measure of all study end points was 1.68 (95% CI, 1.50 to 1.88), ranging from 1.25 (stroke) to 3.53 (CHF). Younger patients (ie, age < 65 years) and female patients had higher risks than older and male participants. COPD was a predictor of CVD hospitalization and mortality over an average follow-up time of nearly 3 years. The finding of a stronger relationship of COPD to CVD outcomes in patients < 65 years of age suggests that CVD risk should be monitored and treated with particular care in younger adults with COPD.

Maternal Autoimmune Diseases, Asthma and Allergies, and Childhood Autism Spectrum Disorders

To investigate the association between physician-documented diagnoses of maternal autoimmune diseases, allergies, and asthma around the time of pregnancy and subsequent diagnoses of autism in children. A case-control study nested within a cohort of infants born between January 1995 and June 1999. Northern California Kaiser Permanente Medical Care Program. Cases (n = 420) were children with at least 1 diagnosis of an autism spectrum disorder (ASD) recorded in Kaiser Permanente outpatient clinical databases. Controls (n = 2100) were children without an ASD diagnosis who were frequency matched to cases on sex, birth year, and hospital of birth. Frequencies of maternal immunologic disorders were compared between cases and controls with a chi2 statistic, and relative risks were estimated by crude and adjusted odds ratios and 95% confidence intervals using logistic regression. The final study population included 407 cases and 2095 controls. A similar proportion of case and control mothers had a diagnosis of any autoimmune disease in the 4-year period surrounding pregnancy (10.3% vs 8.2%, P = .15). After adjustment for maternal factors, only 1 autoimmune condition, psoriasis, was significantly associated with ASDs (adjusted odds ratio, 2.7; 95% confidence interval, 1.3-5.8). A greater than 2-fold elevated risk of ASD was observed for maternal asthma and allergy diagnoses recorded during the second trimester of pregnancy. These findings suggest that maternal autoimmune disorders present in women around the time of pregnancy are unlikely to contribute significantly to autism risk. Further etiologic investigations are needed to confirm these results and should include objective documentation of diagnoses and consider a larger set of maternal immune-related conditions, including asthma and allergies.