Adjacency Matrices of Configuration Graphs

In 1960, Hoffman and Singleton \cite{HS60} solved a celebrated equation for square matrices of order $n$, which can be written as $$(\kappa - 1) I_n + J_n - A A^{\rm T} = A$$ where $I_n$, $J_n$, and $A$ are the identity matrix, the all one matrix, and a $(0,1)$--matrix with all row and column sums equal to $\kappa$, respectively. If $A$ is an incidence matrix of some configuration $\cal C$ of type $n_\kappa$, then the left-hand side $\Theta(A):= (\kappa - 1)I_n + J_n - A A^{\rm T}$ is an adjacency matrix of the non--collinearity graph $\Gamma$ of $\cal C$. In certain situations, $\Theta(A)$ is also an incidence matrix of some $n_\kappa$ configuration, namely the neighbourhood geometry of $\Gamma$ introduced by Lef\`evre-Percsy, Percsy, and Leemans \cite{LPPL}. The matrix operator $\Theta$ can be reiterated and we pose the problem of solving the generalised Hoffman--Singleton equation $\Theta^m(A)=A$. In particular, we classify all $(0,1)$--matrices $M$ with all row and column sums equal to $\kappa$, for $\kappa = 3,4$, which are solutions of this equation. As a by--product, we obtain characterisations for incidence matrices of the configuration $10_3F$ in Kantor's list \cite{Kantor} and the $17_4$ configuration #1971 in Betten and Betten's list \cite{BB99}

Medical use of long-term extended-release opioid analgesics in commercially insured adults in the United States

Objectives. We examined the proportion of patients initiating extended-release (ER) opioids who become long-term users and describe how pain-related diagnoses before initiation of opioid therapy vary between drugs and over time. Methods. Using MarketScan (2006-2015), a US national commercial insurance database, we examined painrelated diagnoses in the 182-day baseline period before initiation of ER opioid therapy to characterize indications for opioid initiation. We report the proportion who became long-term users, the median length of opioid therapy, and the proportion with cancer and other noncancer chronic pain, by active ingredient. Results. Among 1,077,566 adults initiating ER opioids, 31% became long-term users, with a median length of use of 209 days. The most common ER opioids prescribed were oxycodone (26%) and fentanyl (23%), and the most common noncancer pain diagnoses were back pain (65%) and arthritis (48%). Among all long-term users, 16% had a diagnosis of cancer. We found notable variation by drug. Eighteen percent of patients initiating drugs approved by the Food and Drug Administration >10 years ago had evidence of cancer during baseline compared with only 8% of patients who received newer drugs. Conclusions. In a national sample of adults with private insurance, back pain was the most common diagnosis preceding initiation of opioid therapy. Opioids that have been approved within the last 10 years were more frequently associated with musculoskeletal pains and less frequently associated with cancer. Amid increasing concerns regarding long-term opioid therapy, our findings provide context regarding the conditions for which long-term opioid therapy is prescribed

Predictors of prevalent statin use among older adults identified as statin initiators based on Medicare claims data

Purpose: Few studies have evaluated the degree to which prescription drug initiators are correctly identified using claims data. We examine the prevalence and predictors of recent statin possession in statin initiators identified using claims data. Methods: Among Medicare Current Beneficiary Survey (MCBS) respondents, we used Medicare Part D claims from 2006 to 2011 to identify statin initiators using a 12-month baseline period of no prior statin claims. Using MCBS interview data, we identified those with self-reported statins obtained during the baseline period. We used log-binomial regression to estimate adjusted prevalence ratios (adjPR) and 95% confidence intervals (CI) for predictors of recent statin possession. Results: Among 766 statin initiators identified in prescription claims, 155 (20%) reported recent statin possession during baseline. Beneficiaries with no Part D claims in the past 30 days (adjPR = 1.49, 95%CI: 1.13, 1.96), those with no inpatient, outpatient or physician visits in the past 30 days (adjPR = 1.50, 95%CI: 1.11, 2.03), those with a brand name statin index claim (adjPR = 1.55, 95%CI: 1.19, 2.02), and those with an index claim in January or February (adjPR = 1.50, 95%CI: 1.00, 2.26) had an increased probability of recent statin possession. Conclusions: In a cohort of statin initiators identified using prescription claims, 20% had evidence of statin possession during the baseline period. Pharmacoepidemiologic new user studies may benefit from including sensitivity analyses within subgroups less likely to include prevalent users to assess the robustness of key findings to misidentification of the time of treatment initiation

Fluoroquinolone antibiotics and tendon injury in adolescents

OBJECTIVES: To estimate the association between fluoroquinolone use and tendon injury in adolescents. METHODS: We conducted an active-comparator, new-user cohort study using population-based claims data from 2000 to 2018. We included adolescents (aged 12-18 years) with an outpatient prescription fill for an oral fluoroquinolone or comparator broad-spectrum antibiotic. The primary outcome was Achilles, quadricep, patellar, or tibial tendon rupture identified by diagnosis and procedure codes. Tendinitis was a secondary outcome. We used weighting to adjust for measured confounding and a negative control outcome to assess residual confounding. RESULTS: The cohort included 4.4 million adolescents with 7.6 million fills for fluoroquinolone (275 767 fills) or comparator (7 365 684) antibiotics. In the 90 days after the index antibiotic prescription, there were 842 tendon ruptures and 16 750 tendinitis diagnoses (crude rates 0.47 and 9.34 per 1000 person-years, respectively). The weighted 90-day tendon rupture risks were 13.6 per 100 000 fluoroquinolone-treated adolescents and 11.6 per 100 000 comparator-treated adolescents (fluoroquinolone-associated excess risk: 1.9 per 100 000 adolescents; 95% confidence interval 22.6 to 6.4); the corresponding number needed to treat to harm was 52 632. For tendinitis, the weighted 90-day risks were 200.8 per 100 000 fluoroquinolone-treated adolescents and 178.1 per 100 000 comparator-treated adolescents (excess risk: 22.7 per 100 000; 95% confidence interval 4.1 to 41.3); the number needed to treat to harm was 4405. CONCLUSIONS: The excess risk of tendon rupture associated with fluoroquinolone treatment was extremely small, and these events were rare. The excess risk of tendinitis associated with fluoroquinolone treatment was also small. Other more common potential adverse drug effects may be more important to consider for treatment decision-making, particularly in adolescents without other risk factors for tendon injury

The risk of acute pancreatitis after initiation of dipeptidyl peptidase 4 inhibitors: Testing a hypothesis of subgroup differences in older U.S. adults

OBJECTIVE To examine whether dipeptidyl peptidase 4 inhibitors (DPP-4I) increase acute pancreatitis risk in older patients and whether the association varies by age, sex, and history of cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS We conducted a cohort study of DPP-4I initiators versus thiazolidinedione (TZD) or sulfonylurea initiators using U.S.Medicare beneficiaries, 2007-2014. Eligible initiators were aged 66 years or older without history of pancreatic disease or alcohol-related diseases. Patients were followed up for hospitalization due to acute pancreatitis and censored at 90 days after treatment changes. Weighted Cox models were used to estimate the hazard ratio (HR) for acute pancreatitis. Analyses were performed overall as well as within subgroups defined by age, sex, and CVD history. RESULTS We found no increased risk of acute pancreatitis comparing 49,374 DPP-4I initiators to 132,223 sulfonylurea initiators (weighted HR 1.01; 95% CI 0.83-1.24) and comparing 57,301 DPP-4I initiators to 32,612 TZD initiators (weighted HR 1.11; 95% CI 0.76-1.62). Age and sex did not modify the association. Among patients with CVD, acute pancreatitis incidence was elevated in initiators of DPP-4I and sulfonylurea (2.3 and 2.4 per 1,000 person-years, respectively) but not in TZD initiators (1.5). Among patients with CVD, higher risk of acute pancreatitis was observed with DPP- 4I compared with TZD (weighted HR 1.84; 95% CI 1.02-3.35) but not compared with sulfonylurea. CONCLUSIONS Our study provides evidence that DPP-4I is not associated with an increased risk of acute pancreatitis in older adults overall. The positive association observed in patients with CVD could be due to chance or bias but merits further investigation

Trends in opioid and psychotropic prescription in pregnancy in the united states from 2001 to 2015 in a privately insured population: A cross-sectional study

Background: Opioid and psychotropic prescriptions are common during pregnancy. Little is known about coprescriptions of both medications in this setting. Objective: To describe opioid prescription among women who are prescribed psychotropics compared with women who are not. Design: Cross-sectional study. Setting: U.S. commercial insurance beneficiaries from Market- Scan (2001 to 2015). Participants: Pregnant women at 22 weeks' gestation or greater who were insured continuously for 3 months or more before pregnancy through delivery. Measurements: Opioid prescription, dosage thresholds (morphine milligram equivalents [MME] of ≥50/day and ≥90/day), number of opioid agents (≥2), and duration (≥30 days) among those with and without prescription of psychotropics, from 2011 to 2015. Results: Among 958 980 pregnant women, 10% received opioids only, 6% psychotropics only, and 2% opioids with coprescription of psychotropics. Opioid prescription was higher among women prescribed psychotropics versus those who were not (26.5% vs. 10.7%). From 2001 to 2015, psychotropic prescription overall increased from 4.4% to 7.6%, opioid prescription without coprescription of psychotropics decreased from 11.9% to 8.4%, and opioids with coprescription decreased from 28.1% to 22.0%. Morphine milligram equivalents of 50 or greater per day decreased for women with and without coprescription (29.6% to 17.3% and 22.8% to 18.5%, respectively); MME of 90 or greater per day also decreased in both groups (15.0% to 4.7% and 11.5% to 4.2%, respectively). Women prescribed opioids only were more likely to have an antepartum hospitalization compared with those with neither prescription, as were women with coprescription versus those prescribed psychotropics only. Compared with those prescribed opioids only, women with coprescriptions were more likely to exceed MME of 90 or greater per day and to be prescribed 2 or more opioid agents and for 30 days or longer. Number and duration of opioids increased with benzodiazepine and gabapentin coprescription. Limitation: Inability to determine appropriateness of prescribing or overdose events. Conclusion: Opioids are frequently coprescribed with psychotropic medication during pregnancy and are associated with antepartum hospitalization. A substantial proportion of pregnant women are prescribed opioids at doses that increase overdose risk and exceed daily recommendations

Methodological considerations when analysing and interpreting real-world data

In the absence of relevant data from randomized trials, nonexperimental studies are needed to estimate treatment effects on clinically meaningful outcomes. State-of-the-art study design is imperative for minimizing the potential for bias when using large healthcare databases (e.g. claims data, electronic health records, and product/disease registries). Critical design elements include new-users (begin follow-up at treatment initiation) reflecting hypothetical interventions and clear timelines, active-comparators (comparing treatment alternatives for the same indication), and consideration of induction and latent periods. Propensity scores can be used to balance measured covariates between treatment regimens and thus control for measured confounding. Immortal-time bias can be avoided by defining initiation of therapy and follow-up consistently between treatment groups. The aim of this manuscript is to provide a non-technical overview of study design issues and solutions and to highlight the importance of study design to minimize bias in nonexperimental studies using real-world data

Ondansetron use in early pregnancy and the risk of late pregnancy outcomes

Background: The effects of ondansetron, used off-label to treat nausea and vomiting during pregnancy, on common pregnancy complications are understudied. Modest effects of a commonly used drug could result in adverse events for large numbers of pregnant women. Therefore, our objective was to compare the risk of stillbirth, preterm birth, gestational hypertensive disorders, small for gestational age, and differences in birth weight between women prescribed ondansetron and women prescribed alternative antiemetics in early pregnancy. Methods: A cohort of pregnant women receiving a prescription for ondansetron or comparator antiemetics (metoclopramide or promethazine) during the first 20 weeks of pregnancy was identified using electronic health record data from a health care system in North Carolina, USA. Confounding by multiple covariates was controlled using stabilized inverse probability of treatment weights. Weighted hazard ratios (HR) and 95% confidence intervals (CI) accounted for competing events. Results: We identified 2677 eligible pregnancies with antiemetic orders, 66% for ondansetron. The small number of stillbirths (n = 15) resulted in an imprecise estimate of the association with ondansetron (HR = 1.60; 95%CI 0.51, 4.97). No association was observed for preterm birth (HR = 0.90; 95%CI 0.67, 1.20) or gestational hypertensive disorders (HR = 0.87; 95%CI 0.68, 1.12). We observed an association with small for gestational age (HR = 1.37; 95%CI 0.98, 1.90), however mean birth weight among term births was similar between groups. Conclusions: Our results do not suggest that ondansetron increases the risk of preterm birth or gestational hypertensive disorders. The weak association observed between ondansetron use and small for gestational age warrants further investigation

Trends in Pharmacotherapy for Bladder Dysfunction among Children in the United States, 2000 to 2013

Bladder-related issues such as nocturnal enuresis and incontinence have long been a part of general pediatric practice. Increasingly, clinicians are prescribing medications directed at a variety of types of bladder dysfunction, but no prior population-based data exist. We used MarketScan health care claims data on 32 074 638 insured children to estimate utilization patterns by age, sex, year, and geographic region in the United States from 2000 to 2013, and to assess related diagnosis codes. Approximately 1 in 500 children filled an antimuscarinic prescription. The most common prescriptions were for oxybutynin (78%) and tolterodine (17%). Rates were highest at ages 6 to 10 years (65/100 000 person-months), 31% higher for girls versus boys, peaked in 2011 (44/100 000 person-months), and were highest in the Midwest (59/100 000 person-months). Seventy-three percent of children with prescriptions had diagnosis codes for genitourinary symptoms, and 13% had codes for congenital anomalies. Research is needed regarding the comparative effectiveness and safety of these drugs in children

Association of Long-term Child Growth and Developmental Outcomes with Metformin vs Insulin Treatment for Gestational Diabetes

Importance: Metformin is an emerging option for treating gestational diabetes (GDM). However, because metformin crosses the placenta, patients and clinicians are concerned with its long-term effect on child health. Objective: To estimate the association of treating GDM with metformin vs insulin with child growth and development. Design, Setting, and Participants: Population-based cohort study of New Zealand women treated with metformin or insulin for GDM from 2005 to 2012 and their children. This study linked national health care data to create a cohort of mothers and their children, including data from maternity care, pharmaceutical dispensing, hospitalizations, demographic records, and the B4 School Check (B4SC) preschool health assessment. Women treated pharmacologically with metformin or insulin during pregnancy were included. We excluded pregnancies with evidence of diabetes and deliveries prior to 2013. Liveborn infants were linked to their B4SC results. Data were analyzed between January 2017 and May 2018. Exposures: Pharmacologic treatment for GDM with metformin or insulin, measured using pharmaceutical claims data. Main Outcomes and Measures: Child growth (weight and height) and Strengths and Difficulties Questionnaire (SDQ) scores for behavioral development. All outcomes were derived from the B4SC screening program. Linear and log-binomial regression with inverse probability of treatment weighting was used to estimate the association of child growth and psychosocial outcomes with metformin vs insulin treatment for GDM. Results: In both treatment groups, the mean (SD) maternal age was 32 (5) years. A large proportion of mothers who were treated with insulin identified as New Zealand European (867 [44.9%]) while 576 mothers who were treated with metformin (28.9%) identified as New Zealand European. Approximately one-third of mothers who were treated with metformin (n = 639) identified as Asian. We identified 3928 pregnancies treated with metformin (n = 1996) or insulin (n = 1932). After adjustment, we observed no meaningful difference in weight for height z scores between children exposed to metformin compared with insulin (mean difference, -0.10; 95% CI, -0.20 to 0.01). Risk of being 85th percentile or greater for weight for height was similar between treatment groups (adjusted risk ratio, 0.92; 95% CI, 0.83-1.02). Mean SDQ scores were not meaningfully different between the treatment groups, Children of metformin-treated mothers were not significantly more likely to have parent-reported SDQ scores of 14 or more (adjusted risk ratio, 1.13; 95% CI, 0.88-1.46) than those of insulin-treated mothers. Conclusions and Relevance: Our study compares long-term outcomes among school-aged children following maternal use of metformin vs insulin treatment for GDM. Children of metformin-treated mothers were indistinguishable on growth and developmental assessments from those of insulin-treated mothers. These results will help inform future GDM treatment guidelines