Kalotina Machini's research while affiliated with Harvard Medical School and other places

Publications (23)

Article
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Clinical laboratories offering genome sequencing have the opportunity to return pharmacogenomic findings to patients, providing the added benefit of preemptive testing that could help inform medication selection or dosing throughout the lifespan. Implementation of pharmacogenomic reporting must address several challenges, including inherent limitat...
Article
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Over 100 million research participants around the world have had research array-based genotyping (GT) or genome sequencing (GS), but only a small fraction of these have been offered return of actionable genomic findings (gRoR). Between 2017 and 2021, we analyzed genomic results from 36,417 participants in the Mass General Brigham Biobank and offere...
Article
Full-text available
Importance Newborn genomic sequencing (nGS) may provide health benefits throughout the life span, but there are concerns that it could also have an unfavorable (ie, negative) psychosocial effect on families. Objective To assess the psychosocial effect of nGS on families from the BabySeq Project, a randomized clinical trial evaluating the effect of...
Preprint
Full-text available
Over 100 million research participants around the world have had research array-based genotyping (GT) or sequencing (GS), but only a small fraction of these have been offered return of actionable genomic findings (gRoR). Between 2017 and 2021, we analyzed genomic results from 36,417 participants in the Mass General Brigham Biobank and offered to co...
Article
An efficient framework to identify disease-associated genes is needed to evaluate genomic data for both individuals with an unknown disease etiology and those undergoing genomic screening. Here, we propose a framework for gene selection used in genomic analyses, including applications limited to genes with strong or established evidence levels and...
Preprint
Full-text available
An efficient framework to identify disease-causing genes is needed to evaluate genomic data for both individuals with an unknown disease etiology and those undergoing genomic screening. Here, we propose a framework for gene selection used in genomic analyses, including screening applications limited to genes with strong or established evidence leve...
Article
Full-text available
Importance Pathogenic DNA variants associated with familial hypercholesterolemia, hereditary breast and ovarian cancer syndrome, and Lynch syndrome are widely recognized as clinically important and actionable when identified, leading some clinicians to recommend population-wide genomic screening. Objectives To assess the prevalence and clinical im...
Article
Objectives The challenges of understanding how interventions influence follow-up medical care are magnified during genomic testing because few patients have received it to date and because the scope of information it provides is complex and often unexpected. We tested a novel strategy for quantifying downstream healthcare utilization after genomic...
Article
Although genome sequencing is increasingly available in clinical and research settings, many questions remain about the interpretation of sequencing data. In the MedSeq Project, we explored how much effort is required to evaluate and report on more than 4,500 genes reportedly associated with monogenic conditions, as well as pharmacogenomic (PGx) ma...
Article
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Genomic sequencing provides many opportunities in newborn clinical care, but the challenges of interpreting and reporting newborn genomic sequencing (nGS) results need to be addressed for its broader and effective application. The BabySeq Project is a pilot randomized clinical trial that explores the medical, behavioral, and economic impacts of nGS...
Article
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Here, we report a newborn female infant from the well-baby cohort of the BabySeq Project who was identified with compound heterozygous BTD gene variants. The two identified variants included a well-established pathogenic variant (c.1612C>T, p.Arg538Cys) that causes profound biotinidase deficiency (BTD) in homozygosity. In addition, a novel splice v...
Article
Background: There are more than 300 known red blood cell (RBC) antigens and 33 platelet antigens that differ between individuals. Sensitisation to antigens is a serious complication that can occur in prenatal medicine and after blood transfusion, particularly for patients who require multiple transfusions. Although pre-transfusion compatibility te...
Article
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Purpose Great uncertainty exists about the costs associated with whole-genome sequencing (WGS). Methods One hundred cardiology patients with cardiomyopathy diagnoses and 100 ostensibly healthy primary care patients were randomized to receive a family-history report alone or with a WGS report. Cardiology patients also reviewed prior genetic test re...
Article
Purpose Secondary findings from genomic sequencing are becoming more common. We compared how health-care providers with and without specialized genetics training anticipated responding to different types of secondary findings. Methods Providers with genomic sequencing experience reviewed five secondary-findings reports and reported attitudes and p...
Article
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Background: As DNA sequencing costs decline, genetic testing options have expanded. Whole exome sequencing and whole genome sequencing (WGS) are entering clinical use, posing questions about their incremental value compared with disease-specific multigene panels that have been the cornerstone of genetic testing. Methods and results: Forty-one pa...
Article
Background: Whole-genome sequencing (WGS) in asymptomatic adults might prevent disease but increase health care use without clinical value. Objective: To describe the effect on clinical care and outcomes of adding WGS to standardized family history assessment in primary care. Design: Pilot randomized trial. (ClinicalTrials.gov: NCT01736566)....
Article
Purpose: Genomic sequencing (GS) for newborns may enable detection of conditions for which early knowledge can improve health outcomes. One of the major challenges hindering its broader application is the time it takes to assess the clinical relevance of detected variants and the genes they impact so that disease risk is reported appropriately. M...
Article
Full-text available
Recommendations for laboratories to report incidental findings from genomic tests have stimulated interest in such results. In order to investigate the criteria and processes for assigning the pathogenicity of specific variants and to estimate the frequency of such incidental findings in patients of European and African ancestry, we classified pote...
Article
Full-text available
The MedSeq Project is a randomized clinical trial developing approaches to assess the impact of integrating genome sequencing into clinical medicine. To facilitate the return of results of potential medical relevance to physicians and patients participating in the MedSeq Project, we sought to develop a reporting approach for the effective communica...
Article
In recent years, new sequencing technologies known as next generation sequencing (NGS) have provided scientists the ability to rapidly sequence all known coding as well as non-coding sequences in the human genome. As the two emerging approaches, whole exome (WES) and whole genome (WGS) sequencing, have started to be integrated in the clinical arena...

Citations

... Given that the limited amount of data available on population-based health genetic screens demonstrates healthy individuals receive pathogenic results, it is important to recognize that these patients were otherwise unlikely to identify their risk for disease had they not had genetic screening. Zawatsky et al. [30] reported that 76.3% of the individuals who carried pathogenic variants were unaware of their disease risk. Despite not being aware of their risk for disease, patients are still interested in identifying their risk for disease and multiple studies demonstrate that they wish to be alerted to genetic findings of medical importance. ...
... However, it is not clear that the association we found between receiving a diagnosis and a decreased family relationships score has a persistent effect on relationships. Pereira et al. [31], found no persistent negative psychosocial effect on children and families who underwent rGS, compared to other children and families in the NICU who did not undergo rGS. ...
... This procedure proposes a complementary approach to the aggregation of multiple expert-reviewed databases such as DDG2P, Genomic England PanelApp, or ClinGen gene-disease validity available in the GenCC database. 35 However, ClinVarome gene-disease validity confidence is defined for all diseases associated with a gene, which is less precise than curations submitted to the GenCC database. As ClinVarome is a more exhaustive database, this resource could prioritize genes to be curated by GenCC submitters, particularly in the first and second clusters. ...
... The different models were compared both with molecular diagnosis and SB biochemical criteria. The molecular diagnosis of FH was considered as the gold standard, due to the biological definition of the disease, in which FH is characterized as a genetic disorder of lipid metabolism [6], corroborated by evidence from large cohort studies, in which individuals with clinical criteria for FH that are confirmed to have a causative pathogenic variant present a significant increase in the risk of CVD, when compared to clinical FH patients in whom a causative variant is not found [52]. Except for LR algorithm, which can incorporate LLT variable directly in the model, a twobranch training model was implemented for the other classifiers, with separate models built for medicated and non-medicated patients, and testing observations classified according to the appropriate branch. ...
... system. Our results contrast with cost reductions observed in prior studies examining multi-gene panels for treatment de-escalation in earlier-stage cancers or whole genome and whole exome sequencing for diagnosing rare childhood illness (Zambelli et al. 2020;McSorley et al. 2021;Mackay et al. 2020;Vrijenhoek et al. 2018). Additional research is needed to determine whether similar patterns in advanced cancers hold in other jurisdictions. ...
... Female carriers of heterozygous G6PD mutations are at elevated risk of developing acute hemolysis, but could be difficult to recognize by conventional biochemical methods. It has been reported that female carriers identified by genetic screening showed mild phenotypes, which is also observed in our study [41]. Therefore, combined biochemical methods with genetic screening could improve the identification of G6PDD. ...
... Of the 29 studies, 19 did not report eligibility criteria for recruitment of patients (Supplemental Table 2A). Sensitivity analysis limited to the 10 studies that did report eligibility criteria 12,[23][24][25]27,34,[36][37][38]44,46 did not change the overall estimate of efficacy nor heterogeneity (Supplemental Figure 3G). ...
... Blood group typing with WGS is feasible but requires improvements in reading depth for precision typing of single nucleotide variant polymorphisms (123). An automated RBC typing algorithm based on WGS data was 100 % concordant with serological methods for ABO and D antigens and 99.5% accurate at typing the C antigen (124). In the future, WGS may play an essential role in detecting rare blood types and RBC diseases. ...
... As a result of the postlingual onset of KCNQ4-related hearing loss, the effects of a likely pathogenic variant in this gene are not expected to be detected by audiological screening at birth. In another newborn enrolled from the well-baby nursery, 16 nGS identified compound heterozygosity for two BTD variants; one was classified as pathogenic (GenBank: NM_000060.4; c.1612C>T [p.Arg538Cys]) and the other (c.44þ1G>A (p.?)) as a VUS during the initial assessment on the basis of the existence of transcripts without the relevant exon 1 that might abrogate the effects of predicted splicing disruption. ...
... There were slightly fewer outpatient visits for primary care (∆−0.5, 95% CI −3.8 to 0.4, p = 0.66) and cardiology (∆−0.2, 95% CI −0.6 to 0.1, p = 0.13) services in the PGx+ group specifically, but neither difference was statistically significant. Overall, healthcare utilization in this study was consistent with prior assessments of health care service usage within VHA [66][67][68] and for outcomes such as outpatient primary care and cardiology visits and inpatient stays within community settings [69,70]. Utilization and cost data are summarized as mean per-patient estimates. ...