Clinical Practice Patterns in Sickle Cell Disease Treatment: Disease-Modifying and Potentially Curative Therapies.

Therapeutic options for sickle cell disease (SCD) have increased recently as well as the development of updated national guidelines. It is not known how these options are being offered or to what degree guidelines are incorporated into clinical practice. This study aimed to describe practice patterns for pediatric hematologists regarding the use of disease-modifying and potentially curative therapies for SCD. A 9-section, cross-sectional electronic survey was disseminated during a 3-month period via SurveyMonkey, to members of the American Society of Pediatric Hematology/Oncology Hemoglobinopathy Special Interest Group (ASPHO HSIG). A total of 88 physician members of the ASPHO HSIG were surveyed. Ninety percent of respondents (72/80) start hydroxyurea routinely in patients with HbSS and HbSß0 thalassemia, regardless of disease severity. Laboratory monitoring was recommended every 3 months for stable dosing in 63.8% (51/80). New therapies were recommended for patients on hydroxyurea who were still experiencing SCD complications: L-glutamine 68.5% (37/54) or crizanlizumab 93.1% (54/58). Voxelotor was recommended for patients on hydroxyurea with low hemoglobin in 65.1% (43/66) of cases. Matched sibling transplant was considered for any disease severity by 55.1% (38/69). Gene therapy trials are offered on-site by 29% (20/69). Our study demonstrated the enhanced utilization of hydroxyurea while revealing the unexplored potential of other disease-modifying therapies in SCD. These findings underscore the importance of continued knowledge acquisition about the long-term efficacy of new medical therapies and addressing barriers to the use of proven therapies and guide the development of future studies of optimal SCD management.

Venous thromboembolism prophylaxis practices for patients with sickle cell disease prior to and during the COVID-19 pandemic.

Patients with sickle cell disease (SCD) are predisposed to a hypercoagulable state due to alterations in the coagulation system. Despite concern for the development of venous thromboembolism (VTE) in this population, there are no standardized guidelines for routine thromboprophylaxis. The objective of this study was to assess thromboprophylaxis practices of adult and pediatric treaters of SCD before and during the coronavirus disease of 2019 (COVID-19) pandemic. A cross-sectional electronic survey was distributed to pediatric and adult hematology oncology practitioners through seven SCD-specific interest groups between May 29, 2020, and July 13, 2020. Of 93 total responses, 14% ( N  = 13) reported they only treat patients more than 21 years old; 38.7% ( N  = 36) only treat patients 0-21 years old and 47.3% ( N  = 44) reported they treat both. Our study showed that before the COVID-19 pandemic, 96% of adult practitioners would recommend pharmacologic thromboprophylaxis, mechanical thromboprophylaxis or both for hospitalized adults with thromboprophylaxis, but only 76% of pediatric treaters would recommend any thromboprophylaxis in hospitalized children ( P  < 0.0001), with 24% of pediatric treaters choosing no thromboprophylaxis at all. During the COVID-19 pandemic, pharmacologic thromboprophylaxis specifically was recommended for adults by 94% of treaters and for pediatric patients by 76% of treaters. These findings suggest that despite the lack of evidence-based thromboprophylaxis guidelines in adults and children with thromboprophylaxis, subspecialty treaters routinely provide pharmacologic thromboprophylaxis in their adult patients and will modify their practice in pediatric patients who are considered at a high risk for VTE.

Associating a standardized reporting tool for chest radiographs with clinical complications in pediatric acute chest syndrome.

BACKGROUND: Acute chest syndrome (ACS) is an important cause of morbidity in sickle cell disease (SCD). A standardized tool for reporting chest radiographs in pediatric SCD patients did not previously exist. OBJECTIVE: To analyze the interobserver agreement among pediatric radiologists' interpretations for pediatric ACS chest radiographs utilizing a standardized reporting tool. We also explored the association of radiographic findings with ACS complications. METHODS: This was a retrospective cohort study of pediatric ACS admissions from a single institution in 2019. ICD-10 codes identified 127 ACS admissions. Two radiologists independently interpreted the chest radiographs utilizing a standardized reporting tool, a third radiologist adjudicated discrepancies, and κ analysis assessed interobserver agreement. Clinical outcomes were correlated with chest radiograph findings utilizing Pearsons' χ2 , t tests, and Mann-Whitney U tests. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. RESULTS: Interobserver agreement was moderate to near-perfect across variables, with κ analysis showing near-perfect agreement for opacity reported in the right upper lobe (0.84), substantial agreement for right lower lobe (0.63), and vertebral bony changes (0.72), with moderate agreement for all other reported variables. On the initial chest radiograph, an opacity located in the left lower lobe (LLL) correlated with pediatric intensive care unit transfer (p = .03). Pleural effusion on the initial chest radiograph had a 3.98 OR (95% CI: 1.35-11.74) of requiring blood products and a 10.67 OR (95% CI: 3.62-31.39) for noninvasive ventilation. CONCLUSION: The standardized reporting tool showed moderate to near-perfect agreement between radiologists. LLL opacity, and pleural effusion were associated with increased risk of ACS complications.

Impact of magnetic resonance angiography parameters on stroke prevention therapy in pediatric patients with sickle cell anemia.

BACKGROUND: Degree of cerebrovascular stenosis in pediatric patients with sickle cell anemia (SCA) informs need for chronic transfusion therapy, which has significant risks. Flow artifact, intrinsic to magnetic resonance angiography (MRA), is dependent on technical parameters and can lead to overinterpretation of stenosis. The primary objective of this study was to document any change in stroke prevention therapy that could be attributed to the implementation of a standardized MRA scanning protocol for patients with SCA. METHODS: A standardized MRA scanning protocol with an echo time of less than 5 ms was implemented at Montefiore Medical Center (MMC), NY in May 2016. Retrospective chart review identified 21 pediatric patients with SCA, with an MRA head both pre- and post-May 2016. Arterial stenosis on MRA, machine parameters, and treatment plans were compared pre- and post-implementation. RESULTS: Ten of the 21 patients met inclusion criteria. Previously seen stenosis was re-classified to a lower degree in six of the 10 patients, leading to discontinuation of transfusions in five patients. No patients required escalation of therapy to chronic transfusions. CONCLUSION: Optimizing flow artifact by decreasing echo time to less than 5 ms can improve accurate interpretation of cerebrovascular disease, and ensure appropriate treatment plans are in place for stroke prevention. This is especially important for implementing "TCD With Transfusions Changing to Hydroxyurea (TWiTCH)" clinical trial results in the real-world setting.

Demand-only patient-controlled analgesia for treatment of acute vaso-occlusive pain in sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) is a chronic illness that is associated with frequent admissions for vaso-occlusive episodes (VOE). Opioids are frequently utilized in pain management, but dosing is often provider dependent. Opioids cause both short-term and long-term side effects, so the minimal effective dose is desired. This study examined demand-only patient-controlled analgesia (PCA) in pediatric patients. METHODS: A new clinical practice guideline (CPG) for a single institution was implemented, which eliminated basal infusion dosing for PCAs on hospital admission. The primary aim of this retrospective study was to evaluate length of stay (LOS) before and after implementation of a CPG of demand-only PCA and, in a selected subpopulation, addition of short-term methadone. Secondary aims included opioid utilization, acute chest syndrome (ACS), and hypoxia. Inclusion criteria included SCD, ≤21 years of age, uncomplicated VOE admission, and ≥ 3 and ≤ 8 hospital admissions for SCD pain control within one calendar year. RESULTS: LOS decreased postintervention (7.2 ± 5.1 vs 4.5 ± 3.8 days, P < 0.001). Mean total opioid utilization in morphine equivalents mg/kg markedly decreased between the cohorts (13.3 ± 33.8 vs 3.6 ± 3.0, P < 0.001). ACS (21.9% vs 2.8%, P = 0.004) and hypoxia (28% vs 6.9%, P< 0.001) decreased significantly as well. CONCLUSION: Bolus PCA dosing of opioids resulted in decreased LOS and reductions in opioid utilization, hypoxia, and ACS.

Transition Navigator Intervention Improves Transition Readiness to Adult Care for Youth With Sickle Cell Disease.

OBJECTIVE: Adolescents and young adults (AYA) with sickle cell disease (SCD) experience high rates of acute care utilization and increased morbidity. At this high-risk time, they also face the need to transition from pediatric to adult services, which, if poorly coordinated, adds to heightened morbidity and acute care utilization. The study objective was to characterize the feasibility, acceptability, and short-term efficacy of a protocolized transition navigator (TN) intervention in AYA with SCD. METHODS: We developed a protocolized TN intervention that used ecological assessment and motivational interviewing to assess transition readiness, identify goals, and remove barriers to transition, and to provide disease and pain management education and skills to AYAs with SCD. RESULTS: Ninety-three percent (56/60) of enrolled individuals completed the intervention. Participation in the TN program was associated with significant improvement in mean transition readiness scores (3.58-4.15, P < .0001), disease knowledge scale (8.91-10.13, P < .0001), Adolescent Medication Barriers Scale (40.05-35.39, P = .003) and confidence in both disease (22.5-23.96, P = .048) and pain management (25.07-26.61, P = .003) for youth with SCD. CONCLUSION: The TN intervention was acceptable to youth with SCD, feasible to implement at an urban academic medical center, and addressed barriers to transition identified by the youth. Longer-term assessment is needed to determine if the TN intervention improved successful transfer to and retention in adult care.

Clinical outcomes of COVID-19 in patients with sickle cell disease and sickle cell trait: A critical appraisal of the literature.

Individuals with sickle cell disease (SCD) and sickle cell trait (SCT) have many risk factors that could make them more susceptible to COVID-19 critical illness and death compared to the general population. With a growing body of literature in this field, a comprehensive review is needed. We reviewed 71 COVID-19-related studies conducted in 15 countries and published between January 1, 2020, and October 15, 2021, including a combined total of over 2000 patients with SCD and nearly 2000 patients with SCT. Adults with SCD typically have a mild to moderate COVID-19 disease course, but also a 2- to 7-fold increased risk of COVID-19-related hospitalization and a 1.2-fold increased risk of COVID-19-related death as compared to adults without SCD, but not compared to controls with similar comorbidities and end-organ damage. There is some evidence that persons with SCT have increased risk of COVID-19-related hospitalization and death although more studies with risk-stratification and properly matched controls are needed to confirm these findings. While the literature suggests that most children with SCD and COVID-19 have mild disease and low risk of death, some children with SCD, especially those with SCD-related comorbidities, are more likely to be hospitalized and require escalated care than children without SCD. However, children with SCD are less likely to experience COVID-19-related severe illness and death compared to adults with or without SCD. SCD-directed therapies such as transfusion and hydroxyurea may be associated with better COVID-19 outcomes, but prospective studies are needed for confirmation. While some studies have reported favorable short-term outcomes for COVID-19 patients with SCD and SCT, the long-term effects of SARS-CoV-2 infection are unknown and may affect individuals with SCD and SCT differently from the general population. Important focus areas for future research should include multi-center studies with larger sample sizes, assessment of hemoglobin genotype and SCD-modifying therapies on COVID-19 outcomes, inclusion of case-matched controls that account for the unique sample characteristics of SCD and SCT populations, and longitudinal assessment of post-COVID-19 symptoms.

Children and young adults hospitalized for severe COVID-19 exhibit thrombotic coagulopathy.

We report the clinical and laboratory coagulation characteristics of 27 pediatric and young adult patients (2 months to 21 years) treated for symptomatic COVID-19 at a children's hospital in the Bronx, New York, between March 1 and May 31, 2020. D-Dimer was > 0.5 µg/mL (upper limit of normal) in 25 (93%) patients at admission; 11 (41%) developed peak D-dimer > 5 µg/mL during admission. Seven (26%) patients developed venous thromboembolism: three with deep vein thrombosis and four with pulmonary embolism. Requirement of increased ventilatory support was a risk factor for thrombosis (P = 0.006). Three of eight (38%) patients on prophylactic anticoagulation developed thrombosis; however, no patients developed VTE on low-molecular-weight heparin prophylaxis titrated to anti-Xa level. Manifestation of COVID-19 disease was severe or critical in 16 (59%) patients. Four (15%) patients died of COVID-19 complications: all had comorbidities. Elevated D-dimer and increased VTE rate were observed in this young cohort, particularly in those with severe respiratory complications, suggesting thrombotic coagulopathy. More data are needed to guide thromboprophylaxis in this age group.

Association of Anemia and Blood Pressure With Novel Markers of Diastolic Function in Pediatric Sickle Cell Disease.

Diastolic dysfunction is a known cause of mortality in adults with sickle cell disease (SCD). Left atrial function (LAf) and strain (LAS) are novel echocardiographic parameters to assess early diastolic dysfunction, which have not been assessed in pediatric SCD. Through a retrospective single-center study, we describe echocardiographic parameters of diastology in children with SCD and evaluate their relationship with clinical variables including anemia and blood pressure. Baseline clinical data, 24-hour ambulatory blood pressure monitoring data and echocardiography results were collected. LAf and LAS were measured using volumetric data and speckle-tracking echocardiography, respectively. Sixty-seven children with SCD (13.5±7 y, 47% male, 7% hypertensive) with a mean hemoglobin of 8.8±1.3 g/dL, LAf of 61±8% (n=53) and LAS of 46.3±7.4% (n=28) were included. LAS was significantly associated with hemoglobin (ρ=0.43, P=0.022) but not with maximal left atrial (LA) volume (ρ=-0.05, P=0.79) or any blood pressure parameters. On multivariate analysis, LAS decreased by 3.2% (1.3, 5.1) and LA volume increased by 1.6 mL/m2 (3.1, 0.08) for every 1 g/dL decrease in hemoglobin. Thus, severity of baseline anemia in pediatric SCD correlates with diastolic function as measured by LAS, independent of LA dilation.

Efficient Clinical Counseling for Sickle Cell Disease.

Sickle cell anemia (SCA) is a chronic illness that requires frequent health care visits for preventative management. Adherence to national guidelines such as the National Heart Lung and Blood Institute (NHLBI) Expert Panel Report on the Evidence-Based Management of Sickle Cell Disease can be challenging to both the clinician and the patient. Utilizing effective communication strategies with patients and their families can improve clinician/patient relationships, as well as adherence to national guidelines. Aims of this overview are to review challenges faced in outpatient subspecialty medicine and describe evidence-based techniques for more effective communication for patients with sickle cell anemia.

Acute Appendicitis in Pediatric Patients With Sickle Cell Disease: Lower Incidence, More Imaging, and More False-Positives.

OBJECTIVE: Patients with sickle cell disease (SCD) experience recurrent pain crises, which may mimic appendicitis. A prior study found a significantly lower rate of appendicitis in patients with SCD compared with national averages. We investigate the incidence of appendicitis and number of imaging studies for appendicitis in pediatric patients with SCD. METHODS: Using a retrospective study design from a single institution, SCD and control cohorts were created. Inclusion criteria included age 0 to 21years and at least one follow-up appointment within 24 months. Length of observation was calculated from initial presentation to either inpatient admission for appendicitis or last clinic visit. Analysis of an SCD subgroup and a control subset (n = 1,596) was used to compare the number of imaging studies. Incidence rates of appendicitis and number of appendicitis studies were determined. Z-tests, binomial enumeration exact tests, and Fischer's exact tests were used. RESULTS: The SCD cohort included 1,064 patients between January 1, 2001, to December 31, 2014, and the control cohort included 115,109 patients without SCD between January 1, 2011, and December 31, 2011. Incidence rate of appendicitis per 10,000 patient-years was significantly lower in the SCD group compared with controls (2.9 cases versus 10.7 cases per 10,000 patient-years; P = .044). Additionally, the SCD group received significantly more ultrasounds (148 versus 60 per 10,000 patient-years; P< .0001) and CTs (94 versus 27 per 10,000 patient-years; P< .0001) for appendicitis, which remained significant when controlling for race. Patients with SCD also received more false-positive scans. DISCUSSION: Patients with SCD had a significantly lower incidence of appendicitis than controls, yet had a higher number of imaging tests performed for appendicitis. Appendicitis should be viewed as a less common cause of acute abdominal pain in SCD. This consideration should help guide imaging strategy.

Randomized phase 2 trial of Intravenous Gamma Globulin (IVIG) for the treatment of acute vaso-occlusive crisis in patients with sickle cell disease: Lessons learned from the midpoint analysis.

Sickle Cell Disease (SCD) is a chronic hemolytic disorder associated with frequent pain episodes, end organ damage and a shortened lifespan. Currently there exist no disease specific targeted therapies for the treatment of acute vaso-occlusive crisis (VOC) and management with analgesics and hydration is purely supportive. Improvement in understanding of disease pathophysiology has resulted in a great interest in disease modifying novel therapies and many are being evaluated in clinical trials. Here we report the results from the pre-specified mid-point analysis of the Phase 2 study of Intravenous Gamma Globulin (IVIG) for the treatment of acute VOC in patients with SCD and lessons learned.

Acute chest syndrome in the setting of SARS-COV-2 infections-A case series at an urban medical center in the Bronx.

New York City has emerged as one of the epicenters of the SARS-COV-2 pandemic, with the Bronx being disproportionately affected. This novel coronavirus has caused significant respiratory manifestations raising the concern for development of acute chest syndrome (ACS) in patients with sickle cell disease (SCD). We report a series of pediatric SCD SARS-COV-2-positive patients admitted with ACS. SARS-COV-2-positive SCD patients, who did not develop ACS, were the comparison group. Hydroxyurea use (P-value = .02) and lower absolute monocyte counts (P-value = .04) were noted in patients who did not develop ACS. These preliminary findings need to be further evaluated in larger cohorts.

Pulmonary disease burden in Hispanic and non-Hispanic children with sickle cell disease.

RATIONALE: Pulmonary complications are the leading cause of morbidity and mortality in sickle cell disease (SCD) patients. Research in SCD has predominantly been conducted on African-Americans, and the disease burden of SCD in other races and ethnicities, including Hispanic patients, is not well characterized. OBJECTIVE: To compare pulmonary disease burden between Hispanic and non-Hispanic ethnic groups among children with SCD. METHODS: In a retrospective chart review on 566 SCD patients followed at the Children's Hospital at Montefiore, NY, we compared the pulmonary disease burden and disease management in Hispanic patients to their non-Hispanic counterparts. We also compared the contribution of demographic and clinical variables to acute chest syndrome (ACS), vaso-occlusive crisis (VOC), and hospitalizations for SCD related complications between the two ethnic groups. RESULTS: Hispanic patients had a greater proportion of ACS, and had lower forced expiratory volume (FEV1), forced vital capacity, and vital capacity, compared to non-Hispanics. Hispanic patients were more likely to be evaluated in pulmonary clinic and to be on inhaled corticosteroids, short-acting ß agonizts, and leukotriene receptor antagonists. In addition, Hispanic children were more likely to be on hydroxyurea, and receive exchange transfusions. However, the association of asthma with the proportion of ACS did not differ between Hispanics and non-Hispanics. CONCLUSION: Hispanic children with SCD had differences in their pulmonary function profile and received more pulmonary evaluations than non-Hispanic children.

Ambulatory Hypertension in Pediatric Patients With Sickle Cell Disease and Its Association With End-Organ Damage.

Background Sickle cell disease (SCD), a chronic hemolytic disorder, results in cumulative end-organ damage affecting major organs such as the cardiovascular, renal, and central nervous systems. Effects of modifiable risk factors, such as blood pressure (BP), on the development of end-organ complications in SCD have not been well studied, particularly among the pediatric population. Relative hypertension in patients with SCD increases their risks of stroke, cardiovascular complications, and death. The primary hypothesis of this study was that abnormal BP patterns are common among patients with SCD and they impact end-organ complications. Methods Patients with SCD (HbSS, HbSß0) were enrolled from the Children's Hospital at Montefiore (N = 100). For each patient, demographic data were collected, biochemical variables in urine and blood samples were analyzed, BP was determined with ambulatory blood pressure monitoring (ABPM), and an echocardiogram was performed. The prevalence of abnormalities in BP parameters was defined, and their relationships with measures of SCD severity and end-organ damage were assessed. Results Sufficient ABPM data were available for 67 patients. Enrolled children were 13 ± 4 years (40% were males). Assessment of diurnal variation demonstrated that 81% of patients had abnormal systolic nocturnal dipping and 61% had abnormal diastolic nocturnal dipping. Abnormalities in the diurnal pattern were associated with reticulocytosis and hyperfiltration. Microalbuminuria was present in 19% (n = 13) of patients, of which 77% (n = 10) were females (p = 0.014). Diastolic load and abnormal nocturnal dipping were associated with hyperfiltration but not with microalbuminuria. Conclusions BP abnormalities detected with ABPM in SCD patients are prevalent and perhaps are a risk factor for end-organ complications. Further studies are required to identify the mechanisms underlying these relationships and their longitudinal changes.

Airway Inflammation and Lung Function in Sickle Cell Disease.

Rationale: Asthma is a common comorbid condition in sickle cell disease (SCD). However, obstructive lung disease is prevalent in SCD, independent of a diagnosis of asthma. It is speculated that the heightened state of inflammation in SCD, involving pathways distinct from allergic asthma, may underlie the SCD-specific obstructive disease. Objective: The objective of the study was to compare airway and systemic inflammatory markers between SCD patients with pulmonary manifestations and patients with allergic asthma, and correlate the discriminating inflammatory markers with clinical measures of pulmonary disease. Materials and Methods: In a pilot translational study conducted at the Children's Hospital at Montefiore, 15 patients with SCD, and history of asthma, airway obstruction, or airway hyper-reactivity, and 15 control patients with allergic asthma 6-21 years of age were recruited. Inflammatory markers, including peripheral blood T helper cell subsets, serum and exhaled breath condensate (EBC) cytokines and chemokines of the Th-1/Th-17, Th-2, and monocytic pathways, and serum cysteinyl leukotrienes B4 (LTB4), were quantified, compared between the study groups, and correlated with atopic sensitization, pulmonary function tests, and markers of hemolysis. Results: White blood cells (P < 0.05) and monocytes (P < 0.001) were elevated in the SCD group, while atopic characteristics were higher in the control asthma group. Tumor necrosis factor-alpha (P < 0.01), interferon gamma inducible protein (IP)-10 (P < 0.05), and interleukin-4 (P < 0.01) in serum and monocyte chemotactic protein (MCP)-1 in EBC were higher in the SCD group (P ≤ 0.05). Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) in patients with SCD inversely correlated with serum IP-10 and LTB4 levels. Conclusions: Compared with atopic asthmatic patients, inflammatory markers involving Th-1, Th-2, and monocytic pathways were higher in the SCD group, among which Th-1 measures correlated with pulmonary function deficits.

Association Between Periodic Limb Movements in Sleep and Cerebrovascular Changes in Children With Sickle Cell Disease.

STUDY OBJECTIVES: Periodic limb movements (PLMs) have been associated with increased risk of stroke, but there is currently scarce research exploring this relationship in the setting of sickle cell disease (SCD). The aim of this study was to explore whether increased PLMs in children with SCD are associated with increased risk of cerebrovascular disease and to determine if there are any clinical or laboratory differences between children with SCD with elevated periodic limb movement index (PLMI) versus those with normal PLMI. METHODS: This study is a comprehensive review of medical records of 129 children with SCD (aged ≤ 18 years) who had undergone polysomnography for evaluation of sleep-disordered breathing. RESULTS: Elevated PLMI (PLMI > 5 events/h) was present in 42% (54/129) of children with SCD. Children with elevated PLMI were found to have higher percentage of hemoglobin S, lower total iron, higher arousal index and tendency toward elevated transcranial Doppler velocity (P = .063, odds ratio = 3.9, 95% CI 0.93-16.22). While association between elevated PLMI and isolated cerebrovascular stenosis (P = .050, odds ratio 5.6, 95% CI 1.0-31.10) trended toward significance, there was significantly greater proportion of children with elevated PLMI who had cerebrovascular stenosis with Moyamoya disease (P = .046) as demonstrated by magnetic resonance imaging (MRI). CONCLUSIONS: The prevalence of elevated PLMI in children with SCD was higher than in previously published data. Elevated PLMI was significantly associated with greater rates of cerebrovascular disease as detected by MRI.

Misidentification of MLL3 and other mutations in cancer due to highly homologous genomic regions.

The MLL3 gene has been shown to be recurrently mutated in many malignancies including in families with acute myeloid leukemia. We demonstrate that many MLL3 variant calls made by exome sequencing are false positives due to misalignment to homologous regions, including a region on chr21, and can only be validated by long-range PCR. Numerous other recurrently mutated genes reported in COSMIC and TCGA databases have pseudogenes and cannot also be validated by conventional short read-based sequencing approaches. Genome-wide identification of pseudogene regions demonstrates that frequency of these homologous regions is increased with sequencing read lengths below 200 bps. To enable identification of poor quality sequencing variants in prospective studies, we generated novel genome-wide maps of regions with poor mappability that can be used in variant calling algorithms. Taken together, our findings reveal that pseudogene regions are a source of false-positive mutations in cancers.