Quantifying the impact of novel metastatic cancer therapies on health inequalities in survival outcomes.

Background: Novel therapies in metastatic cancers have contributed to improvements in survival outcomes, yet real-world data suggest that improvements may be mainly driven by those patient groups who already had the highest survival outcomes. This study aimed to develop and apply a framework for quantifying the impact of novel metastatic cancer therapies on health inequalities in survival outcomes based on published aggregate data. Methods: Nine (N = 9) novel therapies for metastatic breast cancer (mBC), metastatic colorectal cancer (mCRC), and metastatic non-small cell lung cancer (mNSCLC) were identified, 3 for each cancer type. Individual patient data (IPD) for overall survival (OS) and progression-free survival (PFS) were replicated from published Kaplan-Meier (KM) curves. For each cancer type, data were pooled for the novel therapies and comparators separately and weighted based on sample size to ensure equal contribution of each therapy in the analyses. Parametric (mixture) distributions were fitted to the weighted data to model and extrapolate survival. The inequality in survival was defined by the absolute difference between groups with the highest and lowest survival for 2 stratifications: one for which survival was stratified into 2 groups and one using 5 groups. Additionally, a linear regression model was fitted to survival estimates for the 5 groups, with the regression coefficient or slope considered as the inequality gradient (IG). The impact of the pooled novel therapies was subsequently defined as the change in survival inequality relative to the pooled comparator therapies. A probabilistic analysis was performed to quantify parameter uncertainty. Results: The analyses found that novel therapies were associated with significant increases in inequalities in survival outcomes relative to their comparators, except in terms of OS for mNSCLC. For mBC, the inequalities in OS increased by 13.9 (95% CI: 1.4; 26.6) months, or 25.0%, if OS was stratified in 5 groups. The IG for mBC increased by 3.2 (0.3; 6.1) months, or 24.7%. For mCRC, inequalities increased by 6.7 (3.0; 10.5) months, or 40.4%, for stratification based on 5 groups; the IG increased by 1.6 (0.7; 2.4) months, or 40.2%. For mNSCLC, inequalities decreased by 14.9 (-84.5; 19.0) months, or 12.2%, for the 5-group stratification; the IG decreased by 2.0 (-16.1; 5.1) months, or 5.5%. Results for the stratification based on 2 groups demonstrated significant increases in OS inequality for all cancer types. In terms of PFS, the increases in survival inequalities were larger in a relative sense compared with OS. For mBC, PFS inequalities increased by 8.7 (5.9; 11.6) months, or 71.7%, for stratification based on 5 groups; the IG increased by 2.0 (1.3; 2.6) months, or 67.6%. For mCRC, PFS inequalities increased by 5.4 (4.2; 6.6) months, or 147.6%, for the same stratification. The IG increased by 1.3 (1.1; 1.6) months, or 172.7%. For mNSCLC, inequalities increased by 18.2 (12.5; 24.4) months, or 93.8%, for the 5-group stratification; the IG increased by 4.0 (2.8; 5.4) months, or 88.1%. Results from the stratification based on 2 groups were similar. Conclusion: Novel therapies for mBC, mCRC, and mNSCLC are generally associated with significant increases in survival inequalities relative to their comparators in randomized controlled trials, though inequalities in OS for mNSCLC decreased nonsignificantly when stratified based on 5 groups. Although further research using real-world IPD is warranted to assess how, for example, social determinants of health affect the impact of therapies on health inequalities among patient groups, the proposed framework can provide important insights in the absence of such data.

Radiotherapy-Associated Pelvic Insufficiency Fracture Treated by Romosozumab: Course of CT Attenuations at L1 and L5.

Pelvic radiation therapy (RT) is a risk factor for pelvic insufficiency fracture, which may be accompanied by significant pain, decreased self-sufficiency, and impaired mobility. Assessment of bone density with "opportunistic" computed tomography (CT) attenuation of the L1 vertebral body can be used as a surrogate for dual-energy x-ray absorptiometry (DXA) scan and potentially be useful to follow bone changes in cancer patients who undergo surveillance CT imaging. The following is a case of a 60-year-old female who suffered a pelvic insufficiency fracture, after receiving chemotherapy and pelvic RT for endometrial cancer, for which she was treated with romosozumab, a sclerostin inhibitor used for postmenopausal women at high risk for insufficiency or fragility fracture. CT attenuation of the L1 and L5 vertebral bodies were measured prior to chemoradiation therapy, post-therapy, and before and after treatment with romosozumab. Pelvic RT was associated with declining CT attenuation, greater in magnitude at L5 vs L1 vertebral body, while treatment with romosozumab was associated with increase to baseline at L1, and improvement but not return to baseline at L5.

Biomechanical compensations during a stand-to-sit maneuver using transfemoral osseointegrated prostheses: A case series.

BACKGROUND: Patients with transfemoral amputation and socket prostheses are at a heightened risk of developing musculoskeletal overuse injuries, commonly due to altered joint biomechanics. Osseointegrated prostheses, which involve direct anchorage of the prosthesis to the residual limb through a bone anchored prosthesis, are a novel alternative to sockets yet their biomechanical effect is largely unknown. METHODS: Four patients scheduled to undergo unilateral transfemoral prosthesis osseointegration completed two data collections (baseline with socket prosthesis and 12-months after prosthesis osseointegration) in which whole-body kinematics and ground reaction forces were collected during stand-to-sit tasks. Trunk, pelvis, and hip kinematics, and the surrounding muscle forces, were calculated using subject-specific musculoskeletal models developed in OpenSim. Peak joint angles and muscle forces were compared between timepoints using Cohen's d effect sizes. FINDINGS: Compared to baseline with socket prostheses, patients with osseointegrated prostheses demonstrated reduced lateral trunk bending (d = 1.46), pelvic obliquity (d = 1.09), and rotation (d = 1.77) toward the amputated limb during the stand to sit task. This was accompanied by increased amputated limb hip flexor, abductor, and rotator muscle forces (d> > 0.8). INTERPRETATION: Improved lumbopelvic movement patterns and stabilizing muscle forces when using an osseointegrated prosthesis indicate that this novel prosthesis type likely reduces the risk of the development and/or progression of overuse injuries, such as low back pain and osteoarthritis. We attribute the increased muscle hip muscle forces to the increased load transmission between the osseointegrated prosthesis and residual limb, which allows a greater eccentric ability of the amputated limb to control lowering during the stand-to-sit task.

Analysis of Postoperative Gait, Hip Strength, and Patient-Reported Outcomes After OTA/AO 61-B and 61-C Pelvic Ring Injuries.

OBJECTIVES: To examine clinical gait parameters, hip muscle strength, pelvic functional outcomes, and psychological outcomes after surgical fixation of OTA/AO 61-B and 61-C pelvic ring injuries. DESIGN: Retrospective review identified 10 OTA/AO 61-B patients and 9 OTA/AO 61-C patients for recruitment who were between 1 and 5 years after pelvic fixation. Gait and strength assessments, and patient-reported outcome scores were performed/collected and analyzed. SETTING: Outpatient clinical motion performance laboratory. PATIENTS/PARTICIPANTS: Patients with OTA/AO 61-B and OTA/AO 61-C fractures who were between 1 and 5 years after pelvic fixation. MAIN OUTCOME MEASUREMENTS: Hip strength, kinetics, and spatial-temporal outcomes; Majeed Pelvic Outcome Score; Short Form 36; Hamilton Anxiety/Depression Rating Scales. RESULTS: There were no differences in age, body mass index, or time since definitive fixation between OTA/AO 61-B and 61-C groups. The OTA/AO 61-C group had higher median injury severity scores, longer length of stay, and greater postoperative pelvic fracture displacement. There was no difference in bilateral hip strength, bilateral peak hip moments, peak hip power, and walking speed between groups. Patients with OTA/AO 61-C fractures had lower scores on Short Form 36 General Health and Majeed Work, with a trend toward a lower Total Majeed score. There were no differences in self-reported total anxiety and depression symptoms. CONCLUSIONS: This study did not identify any gait, strength, or psychological differences between OTA/AO 61-B and 61-C injuries at 1-5 years of follow-up. However, increased injury severity in OTA/AO 61-C patients may have residual consequences on perceived general health and ability to work. This pilot study establishes a template for future research into functional recovery of patients with severe pelvic ring trauma. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Real-World Evidence for Control of Chronic Migraine Patients Receiving CGRP Monoclonal Antibody Therapy Added to OnabotulinumtoxinA: A Retrospective Chart Review.

INTRODUCTION: Combination use of onabotulinumtoxinA and calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) has the potential to be more effective than either therapy alone for migraine prevention. METHODS: This retrospective, longitudinal chart review included adults with chronic migraine treated at one clinical site with ≥ 2 consecutive cycles of onabotulinumtoxinA and ≥ 1 month of subsequent combination treatment with CGRP mAbs. Charts at time of mAb prescription (baseline) and up to four visits ~ 3, 6, 9, and 12 months post-baseline were reviewed for safety, tolerability, and outcome measures (monthly headache days [MHDs], headache intensity, and migraine-related disability [MIDAS]). RESULTS: Of 300 charts reviewed, 257 patients met eligibility criteria (mean age: 50 years; 82% women). Average headache frequency was 21.5 MHDs before initiation of onabotulinumtoxinA and 12.1 MHDs before adding CGRP mAb therapy. Prescribed mAbs were erenumab (78%), fremanezumab (6%), and galcanezumab (16%). Over the entire study, patients discontinued CGRP mAb more frequently than onabotulinumtoxinA (23 vs. 3%). Adverse events occurred in 28% of patients, most commonly constipation (9%). Compared with onabotulinumtoxinA alone (baseline), MHDs decreased significantly at all visits (mean decrease: 3.5-4.0 MHDs over ~ 6-12 months of combination treatment); 45.1% of patients had clinically meaningful improvement in migraine-related disability (≥ 5-point reduction in MIDAS score) after ~ 6 months. CONCLUSIONS: In this real-world study, combination treatment with onabotulinumtoxinA and CGRP mAbs was well tolerated, with no new safety signals identified, and was associated with additional clinically meaningful benefits. More real-world and controlled trials should be considered to further assess safety and potential benefits of combination treatment. Video abstract: Real-world data suggests that CGRP inhibitors improve onabotulinumtoxinA efficacy for chronic migraine (MP4 20,067 kb).

Weight and Height in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Longitudinal Database Study Assessing the Impact of Guanfacine, Stimulants, and No Pharmacotherapy.

Objectives: To assess the impact of long-term pharmacotherapy with guanfacine immediate- or extended-release (GXR), administered alone or as an adjunctive to a stimulant, on weight and height in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Methods: Data were extracted from U.S. Department of Defense medical records for patients 4-17 years of age at index date (initiation of any study medication following a year without ADHD medications, or diagnosis if unmedicated) with weight/height measurements for the analysis period (January 2009-June 2013) and the previous year (baseline). Longitudinal weight and height z-scores were analyzed using multivariable regression in three cohorts: guanfacine (initial period of guanfacine exposure), first-line stimulant monotherapy (initial period of exposure), and unmedicated. Guanfacine cohort subgroups were based on previous/concurrent stimulant exposure. Results: The weight analyses included 47,910 patients (66.8% male) and the height analyses 41,248 (67.2% male). Mean initial exposure in the weight analyses was 237 days (standard deviation [SD] = 258, median = 142) for guanfacine and 257 days (SD = 284, median = 151) for first-line stimulant monotherapy, and was similar in the height analyses. Modeling indicated that guanfacine monotherapy was not associated with clinically meaningful deviations from normal z-score trajectories for weight (first-line, n = 943; nonfirst-line, n = 796) or height (first-line, n = 741; nonfirst-line, n = 644). In patients receiving guanfacine adjunctive to a stimulant, modeled weight (n = 1657) and height (n = 1343) z-scores followed declining trajectories. In this subgroup, mean standardized weight/height had decreased during previous stimulant monotherapy. For first-line stimulant monotherapy, modeled weight (n = 32,999) and height (n = 28,470) z-scores followed declining trajectories during year 1. In the unmedicated cohort, modeled weight (n = 11,515) and height (n = 10,050) z-scores were stable. Conclusions: Guanfacine monotherapy (first-line or nonfirst-line) was not associated with marked deviations from normal growth in this modeling study of children and adolescents with ADHD. In contrast, growth trajectories followed an initially declining course with stimulants, whether given alone or with adjunctive guanfacine.

Risk factors for Staphylococcus aureus colonization in a presurgical orthopedic population.

BACKGROUND: Preoperative colonization with Staphylococcus aureus (SA) increases risk of surgical site infection. Screening for SA followed by skin and nasal decolonization can help to reduce the risk of postoperative infections. Risk factors for colonization are, however, not completely understood. METHODS: A case-control study using questionnaires and patient demographics specifically designed to observe SA colonization risk factors in a presurgical orthopedic population. A total of 115 subjects with a positive preoperative screen for SA nasal colonization prior to orthopedic surgery completed a questionnaire to assess for SA risk factors: these subjects served as our cases. An additional 476 controls completed similar questionnaires. Data collected included demographic, health, and lifestyle information. Multivariable logistic regression was used to generate odds ratios (OR) for risk of SA colonization. RESULTS: Several risk factors were identified. Male sex (OR 2.3; 95% confidence interval [CI], [1.4-3.8]) and diabetes (OR 3.8 [1.8-7.8]) significantly increased the risk of SA colonization. Older age, visiting public places (OR 0.2 [0.1-0.3]), recent antibiotic use (OR 0.2 [0.1-0.6]), and the presence of facial hair (OR 0.3 [0.1-0.6]) significantly lowered the risk of SA colonization. CONCLUSIONS: By identifying patients who may be at greater risk of SA colonization, we can better streamline our presurgical techniques to help reduce risk of surgical site infections and improve patient outcomes.

Pregnancy rates and outcomes in women with and without MS in the United States.

OBJECTIVE: To compare pregnancy prevalence and complications in women with and without multiple sclerosis (MS). METHODS: This retrospective US administrative claims study used data from January 1, 2006, to June 30, 2015. All data for women with MS were included. A nationally representative 5% random sample from approximately 58 million women without MS was used to compute the dataset. Annual pregnancy rates, identified via diagnosis/procedure codes and adjusted for covariates, were estimated via logistic regression. Claims for pregnancy and labor/delivery complications were compared using propensity score matching. RESULTS: From 2006 to 2014, the adjusted proportion of women with MS and pregnancy increased from 7.91% to 9.47%; the adjusted proportion without MS and with pregnancy decreased from 8.83% to 7.75%. The difference in linear trend (0.17% increase and 0.15% decrease in per-annum pregnancy rates) was significant (t statistic = 7.8; p < 0.0001). After matching (n = 2,115 per group), a higher proportion of women with MS than without had claims for premature labor (31.4% vs 27.4%; p = 0.005), infection (13.3% vs 10.9%; p = 0.016), cardiovascular disease (3.0% vs 1.9%; p = 0.028), anemia/acquired coagulation disorders (2.5% vs 1.3%; p = 0.007), neurologic complications (1.6% vs 0.6%; p = 0.005), sexually transmitted diseases (0.4% vs 0.1%; p = 0.045), acquired fetal damage (27.8% vs 23.5%; p = 0.002), and congenital fetal malformations (13.2% vs 10.3%; p = 0.004). CONCLUSIONS: Pregnancy rates in this population of women with MS have been increasing. High rates of claims for several peripartum complications were observed in women with and those without MS. Claims data provide knowledge of interactions patients have with the health care system and are valuable initial exploratory analyses.

Transcriptome of the inner circular smooth muscle of the developing mouse intestine: Evidence for regulation of visceral smooth muscle genes by the hedgehog target gene, cJun.

BACKGROUND: Digestion is facilitated by coordinated contractions of the intestinal muscularis externa, a bilayered smooth muscle structure that is composed of inner circular muscles (ICM) and outer longitudinal muscles (OLM). We performed transcriptome analysis of intestinal mesenchyme tissue at E14.5, when the ICM, but not the OLM, is present, to investigate the transcriptional program of the ICM. RESULTS: We identified 3967 genes enriched in E14.5 intestinal mesenchyme. The gene expression profiles were clustered and annotated to known muscle genes, identifying a muscle-enriched subcluster. Using publically available in situ data, 127 genes were verified as expressed in ICM. Examination of the promoter and regulatory regions for these co-expressed genes revealed enrichment for cJUN transcription factor binding sites, and cJUN protein was enriched in ICM. cJUN ChIP-seq, performed at E14.5, revealed that cJUN regulatory regions contain characteristics of muscle enhancers. Finally, we show that cJun is a target of Hedgehog (Hh), a signaling pathway known to be important in smooth muscle development, and identify a cJun genomic enhancer that is responsive to Hh. CONCLUSIONS: This work provides the first transcriptional catalog for the developing ICM and suggests that cJun regulates gene expression in the ICM downstream of Hh signaling. Developmental Dynamics 245:614-626, 2016. © 2016 Wiley Periodicals, Inc.

Computational prediction and experimental validation of novel Hedgehog-responsive enhancers linked to genes of the Hedgehog pathway.

BACKGROUND: The Hedgehog (Hh) signaling pathway, acting through three homologous transcription factors (GLI1, GLI2, GLI3) in vertebrates, plays multiple roles in embryonic organ development and adult tissue homeostasis. At the level of the genome, GLI factors bind to specific motifs in enhancers, some of which are hundreds of kilobases removed from the gene promoter. These enhancers integrate the Hh signal in a context-specific manner to control the spatiotemporal pattern of target gene expression. Importantly, a number of genes that encode Hh pathway molecules are themselves targets of Hh signaling, allowing pathway regulation by an intricate balance of feed-back activation and inhibition. However, surprisingly few of the critical enhancer elements that control these pathway target genes have been identified despite the fact that such elements are central determinants of Hh signaling activity. Recently, ChIP studies have been carried out in multiple tissue contexts using mouse models carrying FLAG-tagged GLI proteins (GLI(FLAG)). Using these datasets, we tested whether a meta-analysis of GLI binding sites, coupled with a machine learning approach, could reveal genomic features that could be used to empirically identify Hh-regulated enhancers linked to loci of the Hh signaling pathway. RESULTS: A meta-analysis of four existing GLI(FLAG) datasets revealed a library of GLI binding motifs that was substantially more restricted than the potential sites predicted by previous in vitro binding studies. A machine learning method (kmer-SVM) was then applied to these datasets and enriched k-mers were identified that, when applied to the mouse genome, predicted as many as 37,000 potential Hh enhancers. For functional analysis, we selected nine regions which were annotated to putative Hh pathway molecules and found that seven exhibited GLI-dependent activity, indicating that they are directly regulated by Hh signaling (78% success rate). CONCLUSIONS: The results suggest that Hh enhancer regions share common sequence features. The kmer-SVM machine learning approach identifies those features and can successfully predict functional Hh regulatory regions in genomic DNA surrounding Hh pathway molecules and likely, other Hh targets. Additionally, the library of enriched GLI binding motifs that we have identified may allow improved identification of functional GLI binding sites.

Role of pharmacoepidemiology studies in addressing pharmacovigilance questions: a case example of pancreatitis risk among ulcerative colitis patients using mesalazine.

PURPOSE: Well-designed pharmacoepidemiology studies address several limitations of postmarketing spontaneous reports in regard to signal evaluation. This study evaluated a signal of disproportionate reporting of acute pancreatitis cases observed in patients with ulcerative colitis (UC) treated with MMX Multi Matrix System® (MMX®) mesalazine and demonstrated how inherent limitations of postmarketing reports were overcome. METHODS: Adults with UC who were new users of MMX mesalazine or another branded mesalazine (controlled-release, delayed-release, or extended-release mesalazine; balsalazide disodium; olsalazine sodium; sulfasalazine; or sulfasalazine delayed-release) were identified from a large US administrative healthcare claims database. Acute pancreatitis incidence rates were compared between patients on MMX mesalazine versus comparator therapies. Propensity scores were used to match patients on MMX mesalazine with patients on comparator drugs to achieve a balance of baseline patient factors. RESULTS: Crude incidence rates [95 % confidence interval (CI)] of acute pancreatitis among patients on MMX mesalazine were similar to those of patients on comparator therapies [8.55 (5.54-13.21) vs 10.05 (7.54-13.41) per 1000 person-years]; the resulting incidence rate ratio (IRR) was [0.85 (0.48-1.47)]. Propensity score-matching had little influence on the IRR [0.84 (0.46-1.55)]; nor did further adjustment by demographic characteristics, daily dose, and causes of acute pancreatitis [0.76 (0.41-1.43)]. CONCLUSION: Findings of no increase in pancreatitis risk with MMX mesalazine demonstrate the value of pharmacoepidemiology studies for evaluating a drug's postmarket safety profile when confronted with spontaneous reporting data suggestive of a safety issue.

Characteristics of patients with non-valvular atrial fibrillation using dabigatran or warfarin in the US.

OBJECTIVE: In order to understand characteristics of atrial fibrillation patients in the era of new oral anticoagulants (NOACs), this study explores differences in characteristics between patients treated with dabigatran etexilate (DE) and warfarin (W) that may be due to patient channeling in 'real-world' clinical practice. RESEARCH DESIGN AND METHODS: Medco claims data were used to characterize 41,805 non-valvular atrial fibrillation (NVAF) patients from the US with a DE (N = 7055) or W (N = 34,750) prescription between February 2011 and April 2012. The first prescription for each treatment in this period defined the index date. The treatment groups were stratified by newly diagnosed or warfarin-experienced patients. Characteristics, comedications, and comorbidities in the 12 month period prior to index date were assessed. RESULTS: Newly diagnosed patients initiating DE had overall lower use of comedications compared to W patients. In contrast, warfarin-experienced patients switching from W to DE showed higher use of antibiotics, beta blockers, gastrointestinal drugs and NSAIDs compared to patients remaining on W. Newly diagnosed NVAF patients initiating DE showed lower proportions for comorbidities such as myocardial infarction, congestive heart failure, and renal disease. This was also reflected in the Charlson comorbidity index (CCI) (mean DE 2.1 vs. W 3.0) and the CHA2DS2-VASc score (mean DE 3.4 vs. W 4.0). For warfarin-experienced NVAF patients, these differences were not seen. Interpretation of results is limited by the fact that administrative claims data are not gathered for scientific research. Underreporting of non-serious conditions might occur and life-style variables, laboratory values and over-the-counter medication were not available. CONCLUSIONS: As also seen for other newly marketed drugs, differences in baseline characteristics, comedication, and comorbidities were detected between DE and W in newly diagnosed patients, as well as in warfarin-experienced patients. This channeling may have significant impact on comparative outcome studies if not properly addressed in study design and analysis.

Impact of health care payer type on HIV stage of illness at time of initiation of antiretroviral therapy in the USA.

There is evidence that earlier initiation of HIV antiretroviral therapy (ART) is associated with better outcomes, including lower morbidity and mortality. Based on recent studies indicating that Medicaid enrollees are more likely to have suboptimal access to medical care, we hypothesized that HIV severity at time of ART initiation is worse for Medicaid patients than patients with other health care coverage. We conducted a US retrospective analysis of GE Centricity Outpatient Electronic Medical Records spanning 1 January 1997 through 30 September 2009. Subjects included all adult HIV patients initiating first-line ART who had CD4+ results within 90 days pre-initiation. HIV stage was defined using CD4 ranges: >500 (n=520), 351-500 (n=379), 201-350 (n=580), or ≤200 (n=406) cells/mm(3), with lower CD4 count being indicative of increased disease severity. Payer type was defined as the patient's primary payer: Medicaid, Medicare, commercial insurance, self-pay or other/unknown. After controlling for demographic and clinical covariates, cumulative logit models assessed the effect of payer type on HIV stage at ART initiation. The study included 1885 subjects with the primary payer being Medicaid (n=218), Medicare (n=330), commercial insurance (n=538), self-pay (n=159) or other/unknown (n=640). Final logit models demonstrated that, compared to patients on Medicaid, the odds of initiating ART at a higher CD4 range were significantly greater for those commercially insured (odds ratio [OR]=1.53; P=0.005), self-paying (OR=1.56; P=0.023) and other/unknown (OR=1.79; P<0.001) and similar for patients enrolled in Medicare (OR=1.11; P=0.521). Medicaid patients initiated ART at a more advanced stage of HIV than patients who were commercially insured, self-paying, or had other/unknown coverage. With HIV treatment guidelines now supporting ART initiation in patients with higher CD4 counts, these findings underscore the need for mitigating barriers, particularly in the Medicaid population, that may delay treatment initiation.

A systematic review of validated methods for identifying erythema multiforme major/minor/not otherwise specified, Stevens-Johnson Syndrome, or toxic epidermal necrolysis using administrative and claims data.

PURPOSE: The Food and Drug Administration's (FDA) Mini-Sentinel pilot program aims to conduct active surveillance to refine safety signals that emerge for marketed medical products. A key facet of this surveillance is to develop and understand the validity of algorithms for identifying health outcomes of interest (HOIs) from administrative and claims data. This paper summarizes the process and findings of the algorithm review of erythema multiforme and related conditions. METHODS: PubMed and Iowa Drug Information Service searches were conducted to identify citations applicable to the erythema multiforme HOI. Level 1 abstract reviews and Level 2 full-text reviews were conducted to find articles that used administrative and claims data to identify erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis and that included validation estimates of the coding algorithms. RESULTS: Our search revealed limited literature focusing on erythema multiforme and related conditions that provided administrative and claims data-based algorithms and validation estimates. Only four studies provided validated algorithms and all studies used the same International Classification of Diseases code, 695.1. Approximately half of cases subjected to expert review were consistent with erythema multiforme and related conditions. CONCLUSIONS: Updated research needs to be conducted on designing validation studies that test algorithms for erythema multiforme and related conditions and that take into account recent changes in the diagnostic coding of these diseases.

A systematic review of validated methods for identifying anaphylaxis, including anaphylactic shock and angioneurotic edema, using administrative and claims data.

PURPOSE: The Food and Drug Administration's Mini-Sentinel pilot program initially aims to conduct active surveillance to refine safety signals that emerge for marketed medical products. A key facet of this surveillance is to develop and understand the validity of algorithms for identifying health outcomes of interest from administrative and claims data. This article summarizes the process and findings of the algorithm review of anaphylaxis. METHODS: PubMed and Iowa Drug Information Service searches were conducted to identify citations applicable to the anaphylaxis health outcome of interest. Level 1 abstract reviews and Level 2 full-text reviews were conducted to find articles using administrative and claims data to identify anaphylaxis and including validation estimates of the coding algorithms. RESULTS: Our search revealed limited literature focusing on anaphylaxis that provided administrative and claims data-based algorithms and validation estimates. Only four studies identified via literature searches provided validated algorithms; however, two additional studies were identified by Mini-Sentinel collaborators and were incorporated. The International Classification of Diseases, Ninth Revision, codes varied, as did the positive predictive value, depending on the cohort characteristics and the specific codes used to identify anaphylaxis. CONCLUSIONS: Research needs to be conducted on designing validation studies to test anaphylaxis algorithms and estimating their predictive power, sensitivity, and specificity.

A systematic review of validated methods for identifying hypersensitivity reactions other than anaphylaxis (fever, rash, and lymphadenopathy), using administrative and claims data.

PURPOSE: The Food and Drug Administration's Mini-Sentinel pilot program aims to conduct active surveillance to refine safety signals that emerge for marketed medical products. A key facet of this surveillance is to develop and understand the validity of algorithms for identifying health outcomes of interest from administrative and claims data. This article summarizes the process and findings of the algorithm review of hypersensitivity reactions. METHODS: PubMed and Iowa Drug Information Service searches were conducted to identify citations applicable to the hypersensitivity reactions of health outcomes of interest. Level 1 abstract reviews and Level 2 full-text reviews were conducted to find articles using administrative and claims data to identify hypersensitivity reactions and including validation estimates of the coding algorithms. RESULTS: We identified five studies that provided validated hypersensitivity-reaction algorithms. Algorithm positive predictive values (PPVs) for various definitions of hypersensitivity reactions ranged from 3% to 95%. PPVs were high (i.e. 90%-95%) when both exposures and diagnoses were very specific. PPV generally decreased when the definition of hypersensitivity was expanded, except in one study that used data mining methodology for algorithm development. CONCLUSIONS: The ability of coding algorithms to identify hypersensitivity reactions varied, with decreasing performance occurring with expanded outcome definitions. This examination of hypersensitivity-reaction coding algorithms provides an example of surveillance bias resulting from outcome definitions that include mild cases. Data mining may provide tools for algorithm development for hypersensitivity and other health outcomes. Research needs to be conducted on designing validation studies to test hypersensitivity-reaction algorithms and estimating their predictive power, sensitivity, and specificity.

A systematic review of validated methods for identifying pulmonary fibrosis and interstitial lung disease using administrative and claims data.

PURPOSE: The Food and Drug Administration's Mini-Sentinel pilot program initially aimed to conduct active surveillance to refine safety signals that emerge for marketed medical products. A key facet of this surveillance is to develop and understand the validity of algorithms for identifying health outcomes of interest (HOIs) from administrative and claims data. This paper summarizes the process and findings of the algorithm review of pulmonary fibrosis and interstitial lung disease. METHODS: PubMed and Iowa Drug Information Service Web searches were conducted to identify citations applicable to the pulmonary fibrosis/interstitial lung disease HOI. Level 1 abstract reviews and Level 2 full-text reviews were conducted to find articles using administrative and claims data to identify pulmonary fibrosis and interstitial lung disease, including validation estimates of the coding algorithms. RESULTS: Our search revealed a deficiency of literature focusing on pulmonary fibrosis and interstitial lung disease algorithms and validation estimates. Only five studies provided codes; none provided validation estimates. Because interstitial lung disease includes a broad spectrum of diseases, including pulmonary fibrosis, the scope of these studies varied, as did the corresponding diagnostic codes used. CONCLUSIONS: Research needs to be conducted on designing validation studies to test pulmonary fibrosis and interstitial lung disease algorithms and estimating their predictive power, sensitivity, and specificity.

A systematic review of validated methods for identifying acute respiratory failure using administrative and claims data.

PURPOSE: The Food and Drug Administration's (FDA) Mini-Sentinel pilot program initially aims to conduct active surveillance to refine safety signals that emerge for marketed medical products. A key facet of this surveillance is to develop and understand the validity of algorithms for identifying health outcomes of interest (HOIs) from administrative and claims data. This paper summarizes the process and findings of the algorithm review of acute respiratory failure (ARF). METHODS: PubMed and Iowa Drug Information Service searches were conducted to identify citations applicable to the anaphylaxis HOI. Level 1 abstract reviews and Level 2 full-text reviews were conducted to find articles using administrative and claims data to identify ARF, including validation estimates of the coding algorithms. RESULTS: Our search revealed a deficiency of literature focusing on ARF algorithms and validation estimates. Only two studies provided codes for ARF, each using related yet different ICD-9 codes (i.e., ICD-9 codes 518.8, "other diseases of lung," and 518.81, "acute respiratory failure"). Neither study provided validation estimates. CONCLUSIONS: Research needs to be conducted on designing validation studies to test ARF algorithms and estimating their predictive power, sensitivity, and specificity.

Stability of Metronidazole Benzoate in SyrSpend SF One-Step Suspension System.

The objective of this study was to determine the stability of metronidazole benzoate suspension in SyrSpend SF One-Step Suspension system. The studied samples were packaged in 60-mL amber plastic prescription bottles, which were stored protected from light under controlled environmental conditions for a period of 360 days. Stability of metronidazole benzoate suspension in SyrSpend SF was assessed based on retention of initial color or appearance, pH of suspension, and recovery of metronidazole benzoate from the packaged product. Duplicate samples were evaluated at each predefined time interval. An assay method by high performance liquid chromatography was validated for its specificity and stability-indicating characteristscs through a forced-degradation study, and was used in metronidazole benzoate assay. Metronidazole benzoate in SyrSpend SF retained its normal appearance of an opaque suspension, with acceptable pH values ranging from 4.43 to 4.53 (range 4.45 +/- 0.5). Recovery of metronidazole benzoate at subsequent time points was within 90% to 110% of inital concentration for samples stored at refrigerated temperature (2 deg C to 8 deg C), and ambient condition (25 deg C/60% relative humidity), with no detectable changes in chromatographic profile for most tested samples. The rates of change in potency for metronidazole benzoate were determined under the assumptions of first-order kinetics, and the time to reach 90% to 110% initial concentration was determined to be 366 days for samples in ambient storage, or 716 days for samples stored at refrigerated temperature. Metronidazole benzoate in SyrSpend SF, which was packaged in amber plastic prescription bottles, is stable for at least 1 year when stored protected from light at ambient condition (25 deg C/60% relative humidity). The shelf life for this product may be extended to 2 years when stored at refrigerated temperature.

Anemia as a predictor of cardiovascular events in patients with elevated serum creatinine.

Patients with anemia and patients with chronic kidney disease have elevated risks for cardiovascular disease. Available studies have been too small to provide details about the relationship or to provide for extensive covariate control. In a large insurance database with linked laboratory values, records of women with serum creatinine >1.2 mg/dl and men with serum creatinine >1.4 mg/dl, identified from July 2000 through June 2003, were sought, and the insurance claims searches for hospitalizations that were associated with myocardial infarction, coronary revascularization, unstable angina, stroke, or congestive heart failure. New onset of dialysis also was sought. Multivariate Poisson regression was used to estimate rate ratios for these events at various hemoglobin (Hb) levels, with adjustment for patient characteristics and previous event history. Among 88,657 patients with high serum creatinine, the risk for hospitalization with myocardial infarction was two to five times higher in anemic (Hb <12 g/dl) patients than in people with Hb from 12.0 to 12.9 g/dl. A similar but less dramatic pattern of higher incidence of coronary revascularization was observed with lower Hb levels. Risks for hospitalization with congestive heart failure declined regularly with increasing Hb levels from a doubling of risk at Hb <10 g/dl to a 61% decrease at 15 g/dl, both relative to 12.0 to 12.9 g/dl. The risk for progression to dialysis was only slightly elevated (7 to 34%) in anemic patients. Anemia raises the risk for cardiovascular disease in patients with elevated serum creatinine.