TABLE 4.

Characteristics of included studies

Author (Year)	Title	Study type	Sample characteristics	Index laboratory testing	Biases
Ferenci et al. (2005) 17	Diagnostic value of quantitative hepatic copper determination in patients with Wilson's disease	Case control*	Individuals with WD, of neuropsychiatric, hepatic, or asymptomatic type, controls without WD and participants with other hepatic pathologies	Hepatic copper was measured by atomic absorption spectroscopy	Given the non‐randomized enrollment and observational nature of the study, potential biases may have existed
Lu et al. (2010) 16	The reassessment of the diagnostic value of 24‐hour urinary copper excretion in children with Wilson's disease	Case control*	The individuals had unknown hepatic pathologies	24‐hour urinary copper was measured by ICP mass spectrometry	Non‐randomization, selection bias of the case‐control design may have led to bias
Mak et al. (2008) 15	Diagnostic accuracy of serum ceruloplasmin in Wilson's disease: determination of sensitivity and specificity by ROC curve analysis among ATP7B‐genotyped subjects	Case control*	Individuals with WD of neuropsychiatric, hepatic, or asymptomatic type, groups with no diagnosis of hepatic or neurological deficit, and normal controls	Ceruloplasmin with nephelometry Beckman Coulter IMMAGE	The nature of clinical reference standards in addition to non‐randomization and low acceptability of results with small sample size may lead to the risk of bias
Merle et al. (2009) 14	Serum ceruloplasmin oxidase activity is a sensitive and highly specific diagnostic marker for Wilson's disease	Case control*	Individuals with WD, neurological or hepatic, with alternative hepatic pathologies, or normal controls	Ceruloplasmin nephelometry Dade Behring	Sample selection, non‐randomization, and case‐control amplify the risk of bias
Nicastro et al. (2010) 11	Re‐evaluation of the diagnostic criteria for Wilson's disease in children with mild liver disease	Case control*	Confirmed WD patients either with asymptomatic family screening or hepatic etiology, with alternative hepatic pathologies, or normal controls	Hepatic copper with flame absorption spectrophotometry; urine copper using flame absorption spectrophotometry; ceruloplasmin using radial immunodiffusion NOR‐Partigen Behring	Case‐control study type increases the risk of non‐randomization and less diverse sample set
Sezer et al. (2014) 12	Is it necessary to re‐evaluate diagnostic criteria for Wilson's disease in children?	Case control*	Patients with hepatic WD, alternative hepatic pathologies, or normal controls	Ceruloplasmin by immunoturbidimetry Roche Modular; urine copper with atomic absorption spectrophotometry AA‐6701F Shimadzu; and hepatic copper by atomic absorption spectrophotometry AA‐6701F Shimadzu	Selection bias, non‐randomization bias may increase the risk of bias or confounders
Xu et al. (2018) 13	The optimal threshold of serum ceruloplasmin in the diagnosis of Wilson's disease: A large hospital‐based study	Cross‐sectional	Patients that underwent ceruloplasmin analysis were eligible to be included, and the tests/records were noted in a hospital center	Beckman Coulter Immage; ceruloplasmin using nephelometry	The cross‐sectional study design leads to increase the risk of selection bias
Yang et al. (2015) 18	Prospective evaluation of the diagnostic accuracy of hepatic copper content, as determined using the entire core of a liver biopsy sample	Prospective cohort	Patients with suspected hepatic WD, family member of people with confirmed WD, or those that had alternative hepatic pathologies	Hepatic copper using atomic absorption spectrophotometry Beijing Purkinje General Instruments	The study had the minimal risk of bias, and the population was most reflective of clinical practice
Zarina et al. (2019) 21	Association of Variants in the CP, ATOX1, and COMMD1 genes with Wilson's disease symptoms in Latvia	Genetic prospective cohort	Patients with WD: asymptomatic, hepatic, neurological/psychiatric, and neurological/hepatic	Direct sequences of the ATOX1, COMMD1, and CP genes; direct DNA sequencing of the ATP7B gene	The study had the minimal risk of bias other than the relatively less sample size as compared to a large genetic cohort study

*All patients were being tested for WD, and the Leipzig criteria were the standard of reference.