We assessed 75,412 potentially eligible subjects. Of these, 984 were excluded because of evidence of a pre-existing diagnosis of an excluding condition before their first electronically recorded HC. Of the excluded subjects, 142 (14%) had a maximum HC over the 95th PCN percentile, and 158 (16%) had a maximum HC under the 5th percentile. There were 404,817 head circumference measurements on 74,428 remaining subjects (Table ).
Demographic characteristics of included subjects.
Identification of Subjects with Pathology
Eighty-five subjects were found to have new diagnoses of pathology before three years of age (Figure ). Of the 85 subjects with IEC or MGCM, 43 subjects had no diagnostic or surgery code and were identified because of the presence of neuroradiology orders or results, or specialist referrals or evaluations.
Flowchart Describing Identification of Subjects with Outcome. IEC (intracranial expansive condition), MGCM (metabolic and genetic conditions associated with macrocephaly).
Description of Diagnoses and Outcomes
Of the 85 subjects with the outcome, 56 had IEC: hydrocephalus (n = 24), chronic subdural hematoma (n = 15), cyst (n = 8), and tumor (n = 9). Twenty-nine had MGCM: neurofibromatosis (n = 8), tuberous sclerosis (n = 5), Beckwith-Wiedemann (n = 4), and 1 or 2 subjects each with the following diagnoses: glutaric aciduria type I, Sturge-Weber syndrome, Sotos syndrome, Fragile X syndrome, Noonan syndrome, Leopard syndrome, Bannayan-Riley-Ruvalcaba syndrome, hemimegalencephaly, X-linked MR associated with MECP2 duplication, and diffuse thickening of the skull with no known syndrome. None of the children with conditions classified as MGCM also had lesions large enough to be considered IEC.
There were 24 subjects who received specific intervention for pathology: 18 underwent surgery, 5 additional subjects did not receive surgery but were referred to social services because of concern for non-accidental trauma, and one was prescribed a special diet. Other subjects received variable degrees of further follow-up and evaluation, ranging from no follow-up for three subjects to multiple specialty evaluations and further neuroimaging.
New diagnoses of IEC or MGCM were found in 0.11% (85/74,428) of the entire study population, with 0.03% (24/74,428) who had pathology with subsequent intervention. The age at diagnosis ranged from 3 days to 1075 days (median, 200 days). Eight subjects were diagnosed before 1 month; eight were diagnosed after 24 months.
Head circumference characteristics of subjects with IEC or MGCM
Subjects with IEC or MGCM had a wide range of head sizes, including some with HC below the 1st percentile. The distributions of maximum HC percentile for subjects with pathology were different from the distribution for subjects without known pathology, but with a large amount of overlap (Figure ).
Figure 2 Distribution of maximum head circumference percentiles by outcome. The gray lines indicate the location of the 95th, 97th, and 99.6th percentiles on the x-axis, which is scaled by z-score. The comparative distribution plots compare the distributions without (more ...)
The sensitivity, specificity, positive predictive value, positive and negative likelihood ratios, number needed to screen and number needed to test varied by threshold and curve source (Tables and ). The negative predictive value was 99.9% for each threshold. The threshold of crossing 6 major percentiles identified 490 (CDC), 556 (WHO) and 130 (PCN) children, but none of these subjects had pathology. Almost all of these children had a corresponding increase in weight and length z-scores of similar magnitude.
Test Characteristics of Selected HC Thresholds for Diagnosis of Children with IEC or MGCM
Test Characteristics of Selected HC Thresholds for Diagnosis of Children with IEC or MGCM Requiring Intervention
Crossing 2 increasing major percentile lines had the highest sensitivity but lowest positive predictive value, 0.1%-0.2% (diagnosis) and < 0.1%-0.1% (intervention). The only threshold with a number needed to test less than 100 for diagnosis of any new pathology was the 99.6th percentile of the CDC curve (NNT = 55). The 99.6th percentile of the PCN curve also had the highest likelihood ratio positive at 16.3 (diagnosis) and 22.0 (intervention), but had low sensitivity (15% diagnosis, 21% intervention).
The sensitivity analysis restricted to those 15,712 children with at least one evaluable HC recorded before 1 month and one after 24 months of age showed similar test characteristics. The cumulative incidence (0.19%) and positive predictive values for diagnosis for the 99.6th percentiles were somewhat higher (CDC 1.5%, WHO 0.9%, PCN 3.4%), but the sensitivity of these criteria were low (CDC 27%, WHO 27%, PCN 23%).
When the 239 subjects diagnosed with BESS were included in the outcome (Table ), the sensitivities (17%-75%), positive predictive values (0.7% - 9.7%) and likelihood ratios positive (1.4-24.6) were higher than for IEC and MGCM alone.
Test Characteristics of Selected HC Percentile Thresholds for Diagnosing Children with IEC, MGCM, or BESS
Description of subjects with pathology below the CDC 95th percentile
There were 46 subjects with pathology with IEC or MGCM whose head circumference was never above the CDC 95th percentile, 13 of whom received intervention. The 25 subjects with IEC (7 with hydrocephalus, 5 with cysts, 9 with subdural hematomas, and 4 with tumors) were diagnosed because of increasing HC percentile, acute altered mental status that led to the diagnosis of underlying chronic subdural hematomas, or other neurologic signs. The 21 subjects with MGCM were primarily diagnosed because of characteristic signs unrelated to head size, such as macroglossia or café-au-lait spots.