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Wieland, Brownstein, Berger, Mandl. Density-equalizing Euclidean minimum spanning trees for the detection of all disease cluster shapes. Proc Natl Acad Sci U S A. 2007;104:9404–9.
Existing disease cluster detection methods cannot detect clusters of all shapes and sizes or identify highly irregular sets that overestimate the true extent of the cluster. We introduce a graph-theoretical method for detecting arbitrarily shaped clusters based on the Euclidean minimum spanning tree of cartogram-transformed case locations, which overcomes these shortcomings. The method is illustrated by using several clusters, including historical data sets from West Nile virus and inhalational anthrax outbreaks. Sensitivity and accuracy comparisons with the prevailing cluster detection method show that the method performs similarly on approximately circular historical clusters and greatly improves detection for noncircular clusters.
Porter, Mandl. Data quality and the electronic medical record: a role for direct parental data entry. Proc AMIA SympProc. 1999:354–8.
INTRODUCTION: The paper and electronic medical record (EMR) have evolved with little scientific inquiry into what effect the informant (clinician or patient) has on the validity of the recorded information. We have previously reported on an electronic interview program that facilitated parents' direct reporting of past medical history data. We sought to define additional data elements that parents could report electronically and to compare parents' electronically entered data to that charted by physicians using the current EMR system. METHODS: A convenience sample of parents was recruited to enter data on history of present illness (HPI) and review of systems (ROS) elements using an electronic interview. Data from the electronic parental interview and information abstracted from the physician EMR were compared to data derived from a face-to-face criterion standard interview. Validity, sensitivity and specificity of each mode of data entry were calculated. RESULTS: 100 of 140 eligible parents (71.4%) participated. Validity of information from the electronic interview was comparable to that charted by emergency physicians for HPI regarding fever and ROS questions. Sensitivity of parents' electronic interview was superior to physicians' charting for ROS elements specific to hydration status. CONCLUSIONS: Improved sensitivity for detection of historical risk factors for illness can be achieved by augmenting the pediatric EMR with a section for direct parental direct data input. Direct parental data input to the EMR should be considered to improve the quality of documentation for medical histories.

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Sun, Wingerde, Kohane, Harary, Mandl, Salem-Schatz, Homer. The challenges of automating a real-time clinical practice guideline. Clin Perform Qual Health Care. 1999;7:28–35.
OBJECTIVE: To elucidate the types of problems encountered during implementation of a World Wide Web-based clinical practice guideline to manage hyperbilirubinemia in newborn infants. DESIGN: Formative assessment of an automated clinical-practice guideline in a large-scale implementation. SETTING: Primary-care clinics and offices, inpatient clinics, and emergency department affiliated with an academic children's hospital. PARTICIPANTS: General pediatricians, neonatologists, pediatric nurses, and computer scientists. RESULTS: Existing guidelines for hyperbilirubinemia management could not be translated directly into web pages. Modifications of the original guidelines were required to represent the clinical intent of the guidelines accurately. In addition, the automated guideline was augmented to incorporate a mechanism for generating clinical encounter forms in order for the system to be accepted into the clinical work flow. Other clinical considerations that influenced the final form of the automated guideline included limitations of computer resources and time constraints during patient encounters. CONCLUSIONS: Many existing guidelines are not amenable to straightforward implementation in automated systems. Strategies to increase the efficacy of the automated guidelines included guideline modifications, as well as careful consideration of the flow of clinical work. Repeated cycles of development and pilot testing are needed to design methods to accommodate the constraints imposed by clinical use.
Pena, Taylor, Fishman, Mandl. Costs and effectiveness of ultrasonography and limited computed tomography for diagnosing appendicitis in children. Pediatrics. 2000;106:672–6.
BACKGROUND: A protocol of ultrasonography (US) followed by computed tomography with rectal contrast (CTRC) has been shown to be 94% accurate in the diagnosis of acute appendicitis in children. OBJECTIVE: To evaluate the changes in patient management and costs of a protocol using US and CTRC in the evaluation of appendicitis in children. DESIGN, SETTING, AND SUBJECTS: Prospective cohort study of 139 children between 3 and 21 years of age who had equivocal clinical findings for acute appendicitis seen in the emergency department of a large, urban pediatric teaching hospital between July 1998 and December 1998. PROTOCOL: Children with equivocal clinical presentations for acute appendicitis were prospectively evaluated with US. Patients with positive findings for acute appendicitis went directly to the operating room. Patients with negative or equivocal findings on US underwent CTRC. Surgical management plans were recorded before imaging, after US, and after CTRC. MAIN OUTCOME MEASURES: Surgical management plans before and after the imaging protocol as well as total hospital direct and indirect costs incurred or saved by each change in management were determined. Costs were obtained through the hospital's cost database and by ratios of costs to charges. RESULTS: Of the 139 children, the protocol resulted in a beneficial change in management in 86 children (61.9%), no change in management in 50 children (36.0%) and an incorrect change in management in 3 children (2.1%). US alone resulted in a beneficial change in management decision in 12/31 children (38.7%), while US followed by CTRC resulted in a beneficial change in management in 74/108 children (68.5%). The protocol resulted in a total cost savings of $78 503.99 or $565/patient. CONCLUSION: A protocol of US followed by CTRC in children with negative or equivocal US examinations results in a high rate of beneficial change in management as well as in total cost savings in children with equivocal clinical presentations for suspected appendicitis.
Ong, Umetsu, Mandl. Consequences of antibiotics and infections in infancy: bugs, drugs, and wheezing. Ann Allergy Asthma Immunol. 2014.
BACKGROUND: The prevalence of asthma has increased alarmingly in the past 2 to 3 decades. Increased antibiotic use in infancy has been suggested to limit exposure to gastrointestinal microbes and to predispose to asthma in later life. OBJECTIVE: To evaluate the association between antibiotic exposure during the first year of life and the development of asthma up to the age of 7 years. METHODS: A retrospective population-based study of a cohort of children enrolled in a nationwide employer-provided health insurance plan from January 1, 1999, through December 31, 2006, in the United States (n = 62,576). We evaluated the association between antibiotic exposure during the first year of life and subsequent development of 3 asthma phenotypes: transient wheezing (began and resolved before 3 years of age), late-onset asthma (began after 3 years of age), and persistent asthma (began before 3 years of age and persisted through 4-7 years of age). RESULTS: Antibiotic use in the first year of life was associated with the development of transient wheezing (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.9-2.2; P .001) and persistent asthma (OR, 1.6; 95% CI, 1.5-1.7; P .001). A dose-response effect was observed. When 5 or more antibiotic courses were received, the odds of persistent asthma doubled (OR, 1.9; 95% CI, 1.5-2.6; P .001). There is no association between antibiotic use and late-onset asthma. CONCLUSION: Antibiotic use in the first year life is associated with an increased risk of early-onset childhood asthma that began before 3 years of age. The apparent effect has a clear dose response. Heightened caution about avoiding unnecessary use of antibiotics in infants is warranted.
Daniel, Heisey-Grove, Gadam, Yih, Mandl, Demaria J A., Platt. Connecting health departments and providers: syndromic surveillance’s last mile. MMWR Morb Mortal Wkly Rep. 2005;54 Suppl:147–50.
INTRODUCTION: A critical need exists for mechanisms to identify and report acute illness clusters to health departments. The Massachusetts Department of Public Health (MDPH) works with partner organizations to conduct syndromic surveillance. This effort is based on CDC's Health Alert Network program and includes automated generation and notification of signals and a mechanism to obtain detailed clinical information when needed. METHODS: Syndromic surveillance partners collect emergency department and ambulatory care data. The principal communications platform between syndromic surveillance partners and MDPH is the Massachusetts Homeland and Health Alert Network (HHAN). This Internet-based application serves as a portal for communication and collaboration and alerts predefined groups of users involved in emergency response. Syndromic surveillance partners' systems report to HHAN by using Public Health Information Network Messaging System events that meet thresholds selected by MDPH. Cluster summaries are automatically posted into a document library. HHAN notifies users by electronic mail, alphanumeric pager, facsimile, or voice communications; users decide how they want to be notified for each level of alert. Discussion threads permit real-time communication among all parties. RESULTS: This automated alert system became operational in July 2004. During July-December 2004, HHAN facilitated communication and streamlined investigation of 15 alerts. CONCLUSION: The system allows rapid, efficient alerting and bidirectional communication among public health and private-sector partners and might be applicable to other public health agencies.
Bourgeois, Murthy, Mandl. Comparative effectiveness research: an empirical study of trials registered in ClinicalTrials.gov. PLoS One. 2012;7:e28820.
BACKGROUND: The $1.1 billion investment in comparative effectiveness research will reshape the evidence-base supporting decisions about treatment effectiveness, safety, and cost. Defining the current prevalence and characteristics of comparative effectiveness (CE) research will enable future assessments of the impact of this program. METHODS: We conducted an observational study of clinical trials addressing priority research topics defined by the Institute of Medicine and conducted in the US between 2007 and 2010. Trials were identified in ClinicalTrials.gov. Main outcome measures were the prevalence of comparative effectiveness research, nature of comparators selected, funding sources, and impact of these factors on results. RESULTS: 231 (22.3%; 95% CI 19.8%-24.9%) studies were CE studies and 804 (77.7%; 95% CI, 75.1%-80.2%) were non-CE studies, with 379 (36.6%; 95% CI, 33.7%-39.6%) employing a placebo control and 425 (41.1%; 95% CI, 38.1%-44.1%) no control. The most common treatments examined in CE studies were drug interventions (37.2%), behavioral interventions (28.6%), and procedures (15.6%). Study findings were favorable for the experimental treatment in 34.8% of CE studies and greater than twice as many (78.6%) non-CE studies (P0.001). CE studies were more likely to receive government funding (P = 0.003) and less likely to receive industry funding (P = 0.01), with 71.8% of CE studies primarily funded by a noncommercial source. The types of interventions studied differed based on funding source, with 95.4% of industry trials studying a drug or device. In addition, industry-funded CE studies were associated with the fewest pediatric subjects (P0.001), the largest anticipated sample size (P0.001), and the shortest study duration (P0.001). CONCLUSIONS: In this sample of studies examining high priority areas for CE research, less than a quarter are CE studies and the majority is supported by government and nonprofits. The low prevalence of CE research exists across CE studies with a broad array of interventions and characteristics.
Pfiffner, Oh, Miller, Mandl. ClinicalTrials.gov as a data source for semi-automated point-of-care trial eligibility screening. PLoS OnePLoS OnePLoS One. 2014;9:e111055.
BACKGROUND: Implementing semi-automated processes to efficiently match patients to clinical trials at the point of care requires both detailed patient data and authoritative information about open studies. OBJECTIVE: To evaluate the utility of the ClinicalTrials.gov registry as a data source for semi-automated trial eligibility screening. METHODS: Eligibility criteria and metadata for 437 trials open for recruitment in four different clinical domains were identified in ClinicalTrials.gov. Trials were evaluated for up to date recruitment status and eligibility criteria were evaluated for obstacles to automated interpretation. Finally, phone or email outreach to coordinators at a subset of the trials was made to assess the accuracy of contact details and recruitment status. RESULTS: 24% (104 of 437) of trials declaring on open recruitment status list a study completion date in the past, indicating out of date records. Substantial barriers to automated eligibility interpretation in free form text are present in 81% to up to 94% of all trials. We were unable to contact coordinators at 31% (45 of 146) of the trials in the subset, either by phone or by email. Only 53% (74 of 146) would confirm that they were still recruiting patients. CONCLUSION: Because ClinicalTrials.gov has entries on most US and many international trials, the registry could be repurposed as a comprehensive trial matching data source. Semi-automated point of care recruitment would be facilitated by matching the registry's eligibility criteria against clinical data from electronic health records. But the current entries fall short. Ultimately, improved techniques in natural language processing will facilitate semi-automated complex matching. As immediate next steps, we recommend augmenting ClinicalTrials.gov data entry forms to capture key eligibility criteria in a simple, structured format.
Pfiffner, Oh, Miller, Mandl. ClinicalTrials.gov as a Data Source for Semi-Automated Point-Of-Care Trial Eligibility Screening. PLoS One. 2014;9:e111055.

BACKGROUND: Implementing semi-automated processes to efficiently match patients to clinical trials at the point of care requires both detailed patient data and authoritative information about open studies. OBJECTIVE: To evaluate the utility of the ClinicalTrials.gov registry as a data source for semi-automated trial eligibility screening. METHODS: Eligibility criteria and metadata for 437 trials open for recruitment in four different clinical domains were identified in ClinicalTrials.gov. Trials were evaluated for up to date recruitment status and eligibility criteria were evaluated for obstacles to automated interpretation. Finally, phone or email outreach to coordinators at a subset of the trials was made to assess the accuracy of contact details and recruitment status. RESULTS: 24% (104 of 437) of trials declaring on open recruitment status list a study completion date in the past, indicating out of date records. Substantial barriers to automated eligibility interpretation in free form text are present in 81% to up to 94% of all trials. We were unable to contact coordinators at 31% (45 of 146) of the trials in the subset, either by phone or by email. Only 53% (74 of 146) would confirm that they were still recruiting patients. CONCLUSION: Because ClinicalTrials.gov has entries on most US and many international trials, the registry could be repurposed as a comprehensive trial matching data source. Semi-automated point of care recruitment would be facilitated by matching the registry's eligibility criteria against clinical data from electronic health records. But the current entries fall short. Ultimately, improved techniques in natural language processing will facilitate semi-automated complex matching. As immediate next steps, we recommend augmenting ClinicalTrials.gov data entry forms to capture key eligibility criteria in a simple, structured format.