Search Criteria:
We searched for clinical trials that investigate acute lymphoblastic leukemia in the pediatric population.  PubMed was searched to identify relevant studies. The search strategy is listed in Appendix 1.  The search was performed on Tuesday, November 10, 2015.


We searched the PubMed database for clinical trials associated with treatments for acute lymphoblastic leukemia in pediatric patients published between 2005 and 2015. The full search strategy is described in Appendix 1. Over 1000 studies were identified based on the initial search criteria. These study abstracts (N=1086) were subsequently screened by CCW WDB, JW, and TEN for inclusion based on the following inclusion exclusion criteria (INSERT INFORMATION HERE RELATED TO SCREENING CRITERIA including this sentence -Studies combining original research with meta-analysis were included so as to not exclude original research.). Disputes over inclusion were resolved via consensus. Initial screening resulted in 885 articles retained for further review.  A random sample of 285 studies was selected for full text coding. Additional studies were excluded during this process (e.g., animal studies, genome-wide association studies, adult survivors of pediatric ALL, and genetic studies). Meta-analyses were excluded to avoid redundancy since the primary constituent studies were included. The remaining 182 articles were retained for coding. (See Prisma Diagram).


We formulated an abstraction manual to standardize the coding process. The coding process was conducted in pairs to ensure that at least two researchers reviewed each study.  Nine specific study characteristics were documented: outcome, measurement device, method of aggregation, primacy of outcome, whether the outcome was a harm or side effect of an intervention, study design, study type, metric, & sample size. With regards to metric, when an outcome element was implicitly specified, we considered it specified. For example, because quantifying survival is, by definition, measuring time to event, specific metric for survival analysis outcomes was always coded as time to event. For survival, remission, and relapse, measurement device was coded as “N/A” because, other than a calendar, there is no measurement device. For outcomes reported using scales (e.g., NCI-CTC), metric was coded as "value at a time point" unless otherwise specified within the body of the article. When coding sample size for studies including non-pediatric-ALL research, all study participants were counted, including adult patients and pediatric patients with a cancer other than ALL. Finally, outcomes were grouped into eight domains for analysis: 1) Survival; 2) Mortality; 3) Remission; 4) Relapse; 5) Response to Treatment; 6) Adverse Event; 7) Cognitive Event; 8) Other.

Descriptive statistics were computed using Stata software was used to analyze frequency of appearance of unique outcomes and the specification of the nine outcome elements outlined in the abstraction manual. Unique outcomes were then placed in the eight broad domains listed above and run through Stata to reveal larger trends in reporting.
In order to structure a visual representation and calculate centrality of clinical outcomes in pediatric leukemia, a matrix was constructed. The foundation of this social network was formed using a basis of frequency of connections across outcomes, termed co-occurrences. Each outcome and the number of times it co-occurred with other specific outcomes were recorded in a spreadsheet. Reviewers C.C.W. and W.D.B. produced the network structure with a symmetrically duplicated matrix, ultimately serving to verify the co-occurrences.
We imported the network matrix onto UCINET and used Netdraw software. Each outcome was uploaded onto the program in the order of total co-occurrences. Thus, each outcome was sized in increasingly larger nodes, the plots of FIGURE **; the larger the size of the node, then the larger number of total co-occurrences this outcome maintains across outcomes in pediatric acute lymphoblastic leukemia. Next, the spring embedding function was applied to group outcomes around the largest nodes. This was accomplished by grouping less connected outcomes around nodes in a pattern of descending number of co-occurrences until the network became too dense for coherency. Next, a superstructure was formed, according to FIGURE **, which represents the social network architecture of outcomes.

Appendix 1:
((((acute AND lymphoblast* AND (leukem* OR leukaem*)) OR "Precursor Cell Lymphoblastic Leukemia-Lymphoma"[Mesh]))
(Infan* OR newborn* OR new-born* OR perinat* OR neonat* OR baby OR baby* OR babies OR toddler* OR minors OR minors* OR boy OR boys OR boyhood OR girl* OR kid OR kids OR child* OR children* OR schoolchild* OR (school[ti] AND child[ti]) OR adolescen* OR juvenil* OR youth* OR teen* OR underage* OR pubescen* OR pediatrics[MeSH Terms] OR pediatric* OR paediatric* OR peadiatric* OR prematur* OR preterm*) Filters: Clinical Trial; Clinical Trial, Phase I; Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV; Controlled Clinical Trial; Randomized Controlled Trial; published in the last 10 years.