Kaiser Permanente Medical Care Program Research Articles

Abstract P369: Relation of Breast Arterial Calcification With Ankle Brachial Index

Presence of breast arterial calcification (BAC) has been shown to be independently associated with increased risk of subclinical cardiovascular disease (CVD), angiographically-defined coronary disease and with incident coronary heart disease, stroke and heart failure. However, a relationship between BAC and peripheral vascular disease has not been established. The ankle brachial index (ABI) is an indicator of the severity of peripheral arterial disease (PAD) that predicts future CVD risk. We utilized cross-sectional data collected at the baseline examination (2012-15) of the MultIethNic Study of BrEast ARterial Calcium Gradation and CardioVAscular Disease (MINERVA Study), a cohort study of 5,145 post-menopausal women who were members of the Kaiser Permanente Medical Care Program of Northern California (KPNC) who were free of clinical CVD at baseline. Presence and gradation (in mg of calcium mass) of BAC in digital mammograms was ascertained with a validated densitometry method. ABI, the average of two ankle systolic pressure readings divided by the average of two brachial systolic pressure readings, was measured by trained and certified personnel after a ten-minute rest. A total of 3,693 women had complete data on all variables of interest; their mean (SD) age was 66 (4) years and 64% were white, 12% African-American, 14% Asian, 9% Latina and 1% mixed or other. While 28.2% presented with any detectable BAC (i.e., BAC mass > 0 mg), 5.4% had an ABI < 0.90. Three women had ABI>1.40 and were excluded from analyses (none had BAC>0). Prevalence of ABI < 0.90 was 4.8% (27/2,653) in women with BAC=0 and 6.9% (72/1,040) in women with any detectable BAC. The Odds Ratio of ABI<0.90 associated with any BAC was 1.39 (95% CI, 1.03-1.89) in a model adjusting for age and race/ethnicity, and was 1.38 (95% CI, 1.02-1.88) in a model with further adjustment for BMI, smoking status, diabetes, hypertension, LDL cholesterol, HDL cholesterol and hs-CRP. However, among women with any detectable BAC, standardized log_BAC mass (mg) was not significantly associated in bivariate linear regression analysis with ABI (slope=-0.0030 [SE=0.0031]; p=0.32). Our study demonstrates (for the first time) an independent association between presence of BAC and ABI indicative of PAD, with no apparent linear dose-response relationship.

Site-specific associations between miRNA expression and survival in colorectal cancer cases.

BackgroundMicroRNAs (miRNA) are small non-coding RNA involved in cellular processes, including cell proliferation and angiogenesis. Thus, miRNA expression may alter survival after diagnosis with colorectal cancer (CRC).ResultsIndividuals diagnosed with stage 1 or stage 2 rectal cancer had worse survival than colon cancer cases diagnosed at stage 1 or stage 2. After adjustment for multiple comparisons, no miRNAs were significantly associated with disease stage. Two miRNAs infrequently expressed in the population and not previously reported were associated with survival after diagnosis with colon cancer (miR-1 HR 2.17 95% CI 1.41, 3.36; and miR-101-3p HR 3.51 95% CI 1.72, 7.15). Among those diagnosed with rectal cancer, 201 miRNAs were associated with survival when the FDR q value was < 0.05. Assessment of 105 previously reported miRNAs associated with prognosis showed that four miRNAs influenced colon cancer survival and 17 influenced survival after a diagnosis with rectal cancer when raw p values were considered.Patients and MethodsThis study includes data from population-based studies of CRC conducted in Utah and the Kaiser Permanente Medical Care Program. A total of 1893 carcinoma and normal paired colorectal mucosa tissue samples were run using the Agilent Human miRNA Microarray V19.0. We assessed miRNA differential expression between paired carcinoma and normal colonic mucosa tissue with CRC- specific survival evaluating stage and site-specific associations after adjusting for age, sex, microsatellite instability tumor status, and AJCC stage.ConclusionsMiRNAs dysregulated for both colon and rectal cancer had a greater impact on survival after a diagnosis with rectal cancer.

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.

Expression Profiles of miRNA Subsets Distinguish Human Colorectal Carcinoma and Normal Colonic Mucosa.

OBJECTIVES:MicroRNAs (miRNAs) are small, non-protein-coding RNA molecules that are commonly dysregulated in colorectal tumors. The objective of this study was to identify smaller subsets of highly predictive miRNAs.METHODS:Data come from population-based studies of colorectal cancer conducted in Utah and the Kaiser Permanente Medical Care Program. Tissue samples were available for 1,953 individuals, of which 1,894 had carcinoma tissue and 1,599 had normal mucosa available for statistical analysis. Agilent Human miRNA Microarray V.19.0 was used to generate miRNA expression profiles; validation of expression levels was carried out using quantitative PCR. We used random forest analysis and verified findings with logistic modeling in separate data sets. Important microRNAs are identified and bioinformatics tools are used to identify target genes and related biological pathways.RESULTS:We identified 16 miRNAs for colon and 17 miRNAs for rectal carcinoma that appear to differentiate between carcinoma and normal mucosa; of these, 12 were important for both colon and rectal cancer, hsa-miR-663b, hsa-miR-4539, hsa-miR-17-5p, hsa-miR-20a-5p, hsa-miR-21-5p, hsa-miR-4506, hsa-miR-92a-3p, hsa-miR-93-5p, hsa-miR-145-5p, hsa-miR-3651, hsa-miR-378a-3p, and hsa-miR-378i. Estimated misclassification rates were low at 4.83% and 2.5% among colon and rectal observations, respectively. Among independent observations, logistic modeling reinforced the importance of these miRNAs, finding the primary principal components of their variation statistically significant (P<0.001 among both colon and rectal observations) and again producing low misclassification rates. Repeating our analysis without those miRNAs initially identified as important identified other important miRNAs; however, misclassification rates increased and distinctions between remaining miRNAs in terms of classification importance were reduced.CONCLUSIONS:Our data support the hypothesis that while many miRNAs are dysregulated between carcinoma and normal mucosa, smaller subsets of these miRNAs are useful and informative in discriminating between these tissues.

MicroRNA profiles in colorectal carcinomas, adenomas and normal colonic mucosa: variations in miRNA expression and disease progression.

MiRNAs are small, non-protein-coding RNA molecules that regulate gene expression either by post-transcriptionally suppressing mRNA translation or by mRNA degradation. We examine differentially expressed miRNAs in colorectal carcinomas, adenomas and normal colonic mucosa. Data come from population-based studies of colorectal cancer conducted in Utah and the Kaiser Permanente Medical Care Program. A total of 1893 carcinoma/normal-paired samples and 290 adenoma tissue samples were run on the Agilent Human miRNA Microarray V19.0 which contained 2006 miRNAs. We tested for significant differences in miRNA expression between paired carcinoma/adenoma/normal colonic tissue samples. Fewer than 600 miRNAs were expressed in >80% of people for colonic tissue; of these 86.5% were statistically differentially expressed between carcinoma and normal colonic mucosa using a false discovery rate of 0.05. Roughly half of these differentially expressed miRNAs showed a progression in levels of expression from normal to adenoma to carcinoma tissue. Other miRNAs appeared to be altered at the normal to adenoma stage, while others were only altered at the adenoma to carcinoma stage or only at the normal to carcinoma stage. Evaluation of the Agilent platform showed a high degree of repeatability (r = 0.98) and reasonable agreement with the NanoString platform. Our data suggest that miRNAs are highly dysregulated in colorectal tissue among individuals with colorectal cancer; the pattern of disruption varies by miRNA as tissue progresses from normal to adenoma to carcinoma.

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.

Antidepressants and testicular cancer

Re-examine association of fluoxetine and paroxetine with risk of testicular cancer noted in drug screening, with 4 years more follow-up and expanded study of these and other antidepressant drugs. In the Kaiser Permanente Medical Care Program in Northern California, 906 men with testicular cancer diagnosed August 1996-December 2010 were compared with 38,253 matched controls with race/ethnicity recorded regarding receipt of antidepressant drugs at least 2 years before diagnosis or control index date. Analyses emphasized duration of use and histological subgroups. With control for race/ethnicity and use of other antidepressant drugs, odds ratios (OR) and 95 % confidence intervals (CI) for associations with testicular cancer were as follows: fluoxetine 1.22 (0.88-1.71), paroxetine 1.19 (0.78-1.83), and 1.21 (0.92-1.58) for all serotonin reuptake inhibitors. There was no statistically significant association with risk of all testicular cancers or their histological subtypes for any individual drug or for tricyclics or all antidepressants combined except for citalopram with all testicular cancers 2.55 (1.43-4.52) and those of mixed histology 4.36 (1.50-12.68) and nefazodone with embryonal cancers 9.79 (1.85-51.81). These could readily be chance findings in the context of the many analyses that were performed. Duration of use was not associated with risk of the drugs and drug groups with sufficient numbers of exposed cases for analysis. We found little evidence to support a testicular carcinogenic effect of fluoxetine, paroxetine, or other antidepressant drugs, but a weakly positive association is not ruled out. The signals in prior screening may have been due to chance and/or uncontrolled confounding.

Risk of Stroke Following Trauma or Infection

Hills NK, Johnston SC, Sidney S, et al. Recent trauma and acute infection as risk factors for childhood arterial ischemic stroke. Ann Neurol. 2012; 72 (12): 850– 858; doi: 10.1002/ana.23688[OpenUrl][1][CrossRef][2][PubMed][3] Investigators at multiple institutions performed a case-control study in order to determine whether recent exposure to trauma or infection were risk factors for the development of arterial ischemic stroke (AIS). The study population included 2.5 million children aged <20 years who were members of Kaiser Permanente Medical Care Program (KPMCP) in Northern California from 1993 to 2007. Cases of AIS were identified from electronic records and confirmed by chart review by 2 neurologists using pre-established clinical and radiologic criteria. Cases were matched to 3 randomly selected controls by age, year of enrollment into KPMCP, and primary care facility. Exposure to trauma (defined as any medical encounter for head or neck … [1]: {openurl}?query=rft.jtitle%253DAnn%2BNeurol%26rft.volume%253D72%26rft.spage%253D850%26rft_id%253Dinfo%253Adoi%252F10.1002%252Fana.23688%26rft_id%253Dinfo%253Apmid%252F23280836%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1002/ana.23688&link_type=DOI [3]: /lookup/external-ref?access_num=23280836&link_type=MED&atom=%2Faapgrand%2F29%2F4%2F39.atom

Patient engagement: the critical catalyst to health reform in the USA

Patient engagement: the critical catalyst to health reform in the USA

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.

Candidate Genes and Risk for CP: A Population-Based Study

Studies suggest that genetic polymorphisms may increase an individual's susceptibility to CP. Most findings have yet to be corroborated in an independent cohort. This case-control study is nested within all 334,333 infants ≥36 wk gestation born at Kaiser Permanente Medical Care Program, 1991-2002. We included only non-Hispanic whites who had a neonatal blood sample available. Case patients (n = 138) were identified from medical records to have spastic or dyskinetic CP. Controls (n = 165) were randomly selected from the population. We genotyped polymorphisms previously associated with CP: inducible NOS (iNOS)-231, apolipoprotein E (apoE) ε2 and ε4 alleles, TNF-α-308, IL-8 -251, lymphotoxin 60, endothelial NOS -922, endothelial protein C receptor 219, mannose-binding lectin 54 and 52, factor V Leiden, methyltetrahydrofolate reductase 1298 and 667, prothrombin 20210, and platelet activator inhibitor 11053. Similar to previous reports, the iNOS-231 T allele (25.7 versus 18.9%, p = 0.04) and the apoE ε4 allele (19.3 versus 13.2%, p = 0.04) were more common in patients with CP than in controls. However, there was no statistically significant association between any genetic polymorphism and CP after correction for multiple comparisons.

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.

Re: A Case-Control Study of Levothyroxine and the Risk of Colorectal Cancer

Responding to the study of Rennert et al. (1), we analyzed levothyroxine in relation to risk of colorectal cancer in the context of our screening of pharmaceuticals for possible carcinogenesis (2) in the Kaiser Permanente Medical Care Program in northern California (KPNC), a comprehensive prepaid health-care system. Rennert et al. (1) found that use of levothyroxine for at least 5 years was associated with a reduced risk in all subjects and that among postmenopausal women, risk was lower among nonusers of hormone therapy (HT) than among users. We performed case–control analyses of colon and rectal/rectosigmoid cancer separately using conditional logistic regression and two-sided statistical tests. The study period was August 1994 through February 2008, and the source cohort was over 90% of KPNC subscribers with at least partial coverage of payment for prescriptions. Cancer case patients (colon: N = 12 207; rectum/rectosigmoid: N = 4729) were identified in the Kaiser Permanente Cancer Registry, a contributor to the Surveillance, Epidemiology, and End Results (SEER) program (http://www.seer.cancer.gov), and prescription dispensing records were obtained from all KPNC outpatient pharmacies. For each case patient, we selected up to 50 risk set control subjects, matched for age, sex, year of cohort entry, and duration of follow-up (colon: N = 608 296; rectum/rectosigmoid: N = 235 925). We duplicated the 5 or more years duration-of-use breakpoint of Rennert et al. (1) but also subdivided the remaining subjects into no use and use of less than 5 years, except when comparing HT users and nonusers. Duration of use was calculated by summing the days’ supply of each prescription dispensed. Lacking menopausal status, we assumed that women older than 55 years were postmenopausal. Use of HT was defined as at least two dispensed prescriptions at any time during the study period before diagnosis or index date. Data on risk factors other than age and sex for colorectal cancer were not readily available, but control for some of these by Rennert et al. (1) made virtually no difference in their main finding. Risk of rectal cancer was more than 30% lower in men who used levothyroxine for at least 5 years, relative to the referent group (Table 1). Risk for colon cancer appeared to be slightly reduced, but this finding was not statistically significant. In women, risk for cancer at both sites appeared slightly reduced, but statistical significance was at best borderline. Among women older than 55 years, risk of colon cancer was virtually the same for users and nonusers of HT. Risk of rectal cancer showed non-statistically significant increases in both groups but was less marked in nonusers of HT. Table 1 Risk of colon and rectal cancer in relation to previous use of levothyroxine* Our findings provide support for a reduction in risk of rectal cancer in men associated with long-term use of levothyroxine. Men who were long-term users were also at lower risk for colon cancer, but the association was weaker and not statistically significant. In women, the associations for both sites were negative and weak with at best borderline statistical significance. The negative associations were not more pronounced among women of menopausal age not on HT.

Are thyroid hormone concentrations at birth associated with subsequent autism diagnosis?

Thyroid hormones substantially influence central nervous system development during gestation. We hypothesized that perturbations of early thyroid profiles may contribute to the development of autism spectrum disorders (ASD). Thyroid pathways could provide a mechanism by which environmental factors that affect the thyroid system may impact autism occurrence or phenotypic expression. We investigated whether thyroxine (T4) levels at birth are associated with subsequent ASD, using two existing California study groups in multivariate analysis. One study group included children born in the San Francisco Bay Area in 1994, with cases identified through the California Department of Developmental Services (DDS) and/or the Kaiser Permanente Medical Care Program of Northern California (244 cases, 266 controls); the other included children born in California in 1995, with cases identified through DDS (310 cases, 518 controls). Matched controls were selected from birth certificate records. This exploratory analysis suggested that infants with very low T4 (<3rd percentile) may have higher ASD risk, although results reached statistical significance only for the 1995 study group (1995: OR = 2.74 (95% CI 1.30-5.75; 1994: OR = 1.71 (95% CI 0.57-5.19). A variety of alternate analyses were conducted with available data, without further resolution of the difference between the two study groups. The results of our study indicate that further studies are warranted to investigate whether thyroid hormone perturbations play a role in the development of ASD by evaluating additional potential confounders and genotype or phenotype in larger studies.

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.

Epidemiology of Apnea and Bradycardia Resolution in Premature Infants

There is little epidemiologic evidence to assess the maturation of respiratory control in premature infants. To measure the success rate or the percentage of infants who have no additional events of various apnea- or bradycardia-free intervals after correcting for gestational age, postmenstrual age of the last apnea or bradycardia event, and the severity of the event. This was a retrospective cohort study of infants born at 34 weeks' gestational age or earlier at 1 of 5 Kaiser Permanente Medical Care Program hospitals between 1998 and 2001. The success rates of various apnea- or bradycardia-free intervals were calculated after stratifying according to gestational age, postmenstrual age of the last event, or event severity. Among the 1403 infants identified in this study, 84.2% did not have an apnea event and 78.5% did not have a bradycardia event after they were otherwise ready for discharge. For the entire cohort, a 95% success rate was statistically reached, with a 7-day apnea- or bradycardia-free interval. Infants with a gestational age of 30 weeks or less had a 5% to 15% lower success rate than infants with a gestational age more than 30 weeks for any given apnea- or bradycardia-free interval. The success rate was reduced by an additional 5% to 10% if the last apnea or bradycardia event occurred at a postmenstrual age of more than 36 weeks. Including only the most severe events slightly improved the success rate of a given interval. The risk of recurrence for apnea or bradycardia differs depending on the gestational age of the infant and the postmenstrual age of the last apnea or bradycardia event.

Antidepressant Use During Pregnancy and Childhood Autism Spectrum Disorders

The prevalence of autism spectrum disorders (ASDs) has increased over recent years. Use of antidepressant medications during pregnancy also shows a secular increase in recent decades, prompting concerns that prenatal exposure may contribute to increased risk of ASD. To systematically evaluate whether prenatal exposure to antidepressant medications is associated with increased risk of ASD. Population-based case-control study. Medical records were used to ascertain case children and control children and to derive prospectively recorded information on mothers' use of antidepressant medications, mental health history of mothers, and demographic and medical covariates. The Kaiser Permanente Medical Care Program in Northern California. A total of 298 case children with ASD (and their mothers) and 1507 randomly selected control children (and their mothers) drawn from the membership of the Kaiser Permanente Medical Care Program in Northern California. ASDs. Prenatal exposure to antidepressant medications was reported for 20 case children (6.7%) and 50 control children (3.3%). In adjusted logistic regression models, we found a 2-fold increased risk of ASD associated with treatment with selective serotonin reuptake inhibitors by the mother during the year before delivery (adjusted odds ratio, 2.2 [95% confidence interval, 1.2-4.3]), with the strongest effect associated with treatment during the first trimester (adjusted odds ratio, 3.8 [95% confidence interval, 1.8-7.8]). No increase in risk was found for mothers with a history of mental health treatment in the absence of prenatal exposure to selective serotonin reuptake inhibitors. Although the number of children exposed prenatally to selective serotonin reuptake inhibitors in this population was low, results suggest that exposure, especially during the first trimester, may modestly increase the risk of ASD. The potential risk associated with exposure must be balanced with the risk to the mother or fetus of untreated mental health disorders. Further studies are needed to replicate and extend these findings.

Triglycerides and Amputation Risk in Patients With Diabetes

OBJECTIVETo determine the association between triglyceride levels and lower-extremity amputation (LEA) risk in a large diabetic cohort.RESEARCH DESIGN AND METHODSThis is a 10-year survey follow-up study (from 1995–2006) of 28,701 diabetic patients with a baseline triglyceride measure. All patients were fully insured members of the Kaiser Permanente Medical Care Program and responded to a survey at baseline that included information on ethnicity, socioeconomic status, education, behavioral factors, and information required to determine type of diabetes. The relationship between triglycerides and time to incident nontraumatic LEA, defined by primary hospitalization discharge or procedures, was evaluated using Cox proportional hazards models.RESULTSTriglyceride level was an independent, stepwise risk factor for nontraumatic LEAs within this large diabetic cohort: triglycerides 150–199 mg/dL, hazard ratio (HR) 1.10 (95% CI 0.92–1.32); 200–499 mg/dL, 1.27 (1.10–1.47); >500 mg/dL, 1.65 (1.30–2.10) (reference <150 mg/dL).CONCLUSIONSHypertriglyceridemia is a significant risk factor for LEA in diabetic patients even after controlling for known socioeconomic, health behavioral, and clinical factors. This previously unrecognized clinical risk needs to be further investigated to determine if treatment of triglycerides can reduce amputation risk.