Interview Drill

106 of 106 questions

• Explain the difference between FDR and FWER. When would you pick one over the other?

  Statistics

  technical

  mid

• Walk me through how you'd power a single-cell DE analysis between two conditions.

  Statistics

  technical

  senior

• What's the difference between a p-value and an effect size? Why does the field over-rely on p-values?

  Statistics

  technical

  mid

• Define a confounder. How do you detect one in an observational omics dataset?

  Statistics

  technical

  mid

• When would you use a negative binomial vs Poisson for RNA-seq counts?

  Statistics

  technical

  mid

• Explain Simpson's paradox with a biological example.

  Statistics

  technical

  senior

• What is a permutation test and when does it beat a parametric test?

  Statistics

  technical

  mid

• How would you correct for batch effects in a multi-site cohort?

  Statistics

  technical

  senior

• What's the assumption behind a Cox proportional hazards model, and how do you test it?

  Statistics

  technical

  senior

• Explain bootstrap vs jackknife. Which gives tighter CIs for small samples?

  Statistics

  technical

  mid

• Walk me through your standard scRNA-seq QC pipeline.

  Single-cell

  technical

  mid

• Seurat vs Scanpy — which do you use day-to-day and why?

  Single-cell

  technical

  mid

• How do you choose number of PCs for UMAP?

  Single-cell

  technical

  junior

• Explain the math behind Harmony integration in 2 minutes.

  Single-cell

  technical

  senior

• When is RNA velocity misleading?

  Single-cell

  technical

  senior

• Compare scVI, scANVI, and totalVI. When would you reach for each?

  Single-cell

  technical

  senior

• How do you annotate cell types without a reference atlas?

  Single-cell

  technical

  mid

• Walk me through CellRanger output — what files matter and why?

  Single-cell

  technical

  junior

• How do you analyze CITE-seq or multi-modal data?

  Single-cell

  technical

  senior

• Pseudobulk DE vs single-cell DE — pros and cons.

  Single-cell

  technical

  mid

• How do you detect doublets and what tool do you trust?

  Single-cell

  technical

  mid

• Explain trajectory inference. When does Monocle3 fail?

  Single-cell

  technical

  senior

• Walk me through a germline variant calling pipeline.

  Variant calling / GWAS

  technical

  mid

• GATK Best Practices: what changed in the last 3 years?

  Variant calling / GWAS

  technical

  senior

• How do you call somatic mutations in tumor-normal? Tumor-only?

  Variant calling / GWAS

  technical

  senior

• Explain VQSR. When do you skip it?

  Variant calling / GWAS

  technical

  senior

• How would you find structural variants in long-read data?

  Variant calling / GWAS

  technical

  senior

• What's the difference between population stratification and cryptic relatedness in GWAS?

  Variant calling / GWAS

  technical

  senior

• Walk me through computing a polygenic risk score for a non-European cohort.

  Variant calling / GWAS

  technical

  senior

• What does Hardy-Weinberg equilibrium tell you about a variant?

  Variant calling / GWAS

  technical

  junior

• Explain imputation. What reference panel would you use for African genomes?

  Variant calling / GWAS

  technical

  senior

• How do you handle multi-allelic sites in a VCF?

  Variant calling / GWAS

  coding

  mid

• BWA-MEM vs Minimap2 vs STAR — when do you reach for each?

  RNA-seq

  technical

  mid

• Salmon vs Kallisto vs STAR+featureCounts. Pros and cons of pseudo-alignment.

  RNA-seq

  technical

  mid

• DESeq2 vs edgeR vs limma-voom. When would you pick limma-voom?

  RNA-seq

  technical

  mid

• How do you handle low-count genes before DE?

  RNA-seq

  technical

  junior

• Explain how DESeq2 estimates dispersion.

  RNA-seq

  technical

  senior

• GSEA vs over-representation analysis. When is ORA misleading?

  RNA-seq

  technical

  mid

• How would you detect novel splice junctions?

  RNA-seq

  technical

  senior

• Bulk RNA-seq deconvolution — name 3 methods and their key assumption.

  RNA-seq

  technical

  senior

• Walk me through AlphaFold2's architecture at a high level.

  Structural biology

  technical

  senior

• When would you NOT trust an AlphaFold prediction?

  Structural biology

  technical

  mid

• ESM-2 vs ProtBERT — which would you use for variant effect prediction?

  Structural biology

  technical

  senior

• Explain the difference between docking and molecular dynamics.

  Structural biology

  technical

  mid

• How would you design a protein binder de novo?

  Structural biology

  technical

  senior

• RFdiffusion vs ProteinMPNN — what does each solve?

  Structural biology

  technical

  senior

• Walk me through a CRISPR screen QC pipeline.

  CRISPR / editing

  technical

  mid

• Pooled vs arrayed CRISPR screens — when to use each?

  CRISPR / editing

  technical

  senior

• How do you design guide RNAs and which scoring metric do you trust?

  CRISPR / editing

  technical

  mid

• Explain base editing vs prime editing. Off-target profile differences?

  CRISPR / editing

  technical

  senior

• How would you analyze a Perturb-seq experiment?

  CRISPR / editing

  technical

  senior

• What's the difference between CLIA, CAP, and ISO 15189?

  Clinical / regulatory

  technical

  senior

• Walk me through validating a clinical NGS assay end-to-end.

  Clinical / regulatory

  technical

  senior

• ACMG variant classification — what evidence codes matter most?

  Clinical / regulatory

  technical

  senior

• How is a 21 CFR Part 11 compliant pipeline different from a research pipeline?

  Clinical / regulatory

  technical

  senior

• What is GxP and which of GMP / GLP / GCP applies to bioinformatics?

  Clinical / regulatory

  technical

  mid

• Why does cross-validation leak in genomics data?

  Machine learning

  technical

  senior

• Explain SHAP vs LIME for interpreting a clinical risk model.

  Machine learning

  technical

  senior

• Class imbalance in a rare-disease classifier — what's your approach?

  Machine learning

  technical

  mid

• How would you fine-tune a protein language model on a 5K-sequence assay?

  Machine learning

  technical

  senior

• Compare diffusion models vs VAEs for molecule generation.

  Machine learning

  technical

  senior

• What's the difference between transduction and induction in ML?

  Machine learning

  technical

  senior

• How would you validate a deep-learning histopathology model for FDA submission?

  Machine learning

  technical

  principal

• Snakemake vs Nextflow vs WDL. Which would you pick for a 1000-sample run on GCP?

  Pipelines / system design

  technical

  senior

• Design a scalable pipeline to process 100K WGS samples a year.

  Pipelines / system design

  case

  principal

• How do you handle failed jobs in a distributed pipeline?

  Pipelines / system design

  technical

  mid

• Containers (Docker/Singularity) vs Conda envs — trade-offs for reproducibility?

  Pipelines / system design

  technical

  mid

• Design a data lake for multi-omics + clinical metadata.

  Pipelines / system design

  case

  principal

• Write a function that returns the reverse complement of a DNA string.

  Coding

  coding

  junior

• Parse a VCF and return variants with AF > 0.05. Discuss complexity.

  Coding

  coding

  mid

• Given a BED file and a SAM file, compute coverage per interval. Stream it — assume both are huge.

  Coding

  coding

  senior

• Implement pairwise sequence identity for k sequences. O(k²L) is the obvious answer — make it faster.

  Coding

  coding

  senior

• Find the longest common subsequence between two protein sequences.

  Coding

  coding

  mid

• Given a GTF file, return all transcripts longer than 5kb that overlap a given region.

  Coding

  coding

  mid

• Implement k-mer counting with O(N) memory for an arbitrary genome.

  Coding

  coding

  senior

• SQL: given a `samples` table and a `variants` table, find variants present in >5 samples but absent in healthy controls.

  Coding

  coding

  mid

• Tell me about a time you disagreed with your PI or manager. How did you resolve it?

  Behavioral / leadership

  behavioral

  mid

• Walk me through a project that failed. What did you do differently next time?

  Behavioral / leadership

  behavioral

  mid

• Describe the most ambiguous problem you've worked on.

  Behavioral / leadership

  behavioral

  senior

• Tell me about a time you had to explain a complex result to a non-technical stakeholder.

  Communication

  behavioral

  mid

• Describe a time you had to push back on a wet-lab partner's experimental design.

  Communication

  behavioral

  senior

• Tell me about a time you missed a deadline.

  Behavioral / leadership

  behavioral

  mid

• How do you prioritize when 3 PIs want their analysis done first?

  Behavioral / leadership

  behavioral

  senior

• Tell me about your biggest scientific contribution to date.

  Behavioral / leadership

  behavioral

  senior

• Describe a time you mentored someone — what worked, what didn't?

  Behavioral / leadership

  behavioral

  senior

• How do you handle being the only computational person in a wet-lab team?

  Communication

  behavioral

  mid

• What's the most interesting paper you've read in the last 6 months and why?

  Literature / papers

  behavioral

  mid

• Critique a paper from our group — pick any one.

  Literature / papers

  scientific

  senior

• Walk me through the original AlphaFold2 Nature paper's key innovation vs prior work.

  Literature / papers

  scientific

  senior

• Walk me through a TCR repertoire analysis pipeline.

  Oncology / immunology

  technical

  senior

• How do you estimate tumor mutational burden (TMB)?

  Oncology / immunology

  technical

  mid

• Explain HLA typing from short reads.

  Oncology / immunology

  technical

  senior

• How would you predict neoantigens for a personalized cancer vaccine?

  Oncology / immunology

  case

  senior

• What is microsatellite instability and how do you call it from sequencing?

  Oncology / immunology

  technical

  mid

• What computational metrics matter when designing an mRNA sequence?

  mRNA / delivery

  technical

  mid

• Explain codon optimization. What are the trade-offs?

  mRNA / delivery

  technical

  mid

• How would you model LNP formulation efficiency from sequence + lipid features?

  mRNA / delivery

  case

  senior

• What are your salary expectations?

  Negotiation / HR

  hr

  mid

• Why are you leaving your current role?

  Negotiation / HR

  hr

  junior

• Walk me through your decision matrix for choosing between two offers.

  Negotiation / HR

  hr

  senior

• What's your notice period and earliest start date?

  Negotiation / HR

  hr

  junior

• How important is equity vs base salary to you?

  Negotiation / HR

  hr

  senior

• Why our company over a Big Pharma competitor?

  Negotiation / HR

  hr

  mid

• How do you make a paper's analysis reproducible end-to-end?

  Reproducibility

  technical

  mid

• What's wrong with `pip install` in a published Nature Methods paper?

  Reproducibility

  technical

  mid

• Explain how you'd version both code AND data for a 5-year regulatory submission.

  Reproducibility

  case

  senior